Journal of Immunology Research
Volume 2018 (2018), Article ID 1467538, 14 pages
https://doi.org/10.1155/2018/1467538

Review Article

The Regulation of Inflammation by Innate and Adaptive Lymphocytes

David Alex Cronkite¹ and Tara M. Strutt²

¹College of Medicine, University of Central Florida, 6900 Lake Nona Boulevard, Orlando, FL 32827, USA
²Immunity and Pathogenesis Division, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, 6900 Lake Nona Boulevard, Orlando, FL 32827, USA

Correspondence should be addressed to Tara M. Strutt; tara.strutt@ucf.edu

Received 16 March 2018; Accepted 16 May 2018; Published 11 June 2018

Academic Editor: Yuejin Liang

Copyright © 2018 David Alex Cronkite and Tara M. Strutt. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

Inflammation plays an essential role in the control of pathogens and in shaping the ensuing adaptive immune responses. Traditionally, innate immunity has been described as a rapid response triggered through generic and nonspecific means that by definition lacks the ability to remember. Recently, it has become clear that some innate immune cells are epigenetically reprogrammed or “imprinted” by past experiences. These “trained” innate immune cells display altered inflammatory responses upon subsequent pathogen encounter. Remembrance of past pathogen encounters has classically been attributed to cohorts of antigen-specific memory T and B cells following the resolution of infection. During recall responses, memory T and B cells quickly respond by proliferating, producing effector cytokines, and performing various effector functions. An often-overlooked effector function of memory CD4 and CD8 T cells is the promotion of an inflammatory milieu at the initial site of infection that mirrors the primary encounter. This memory-conditioned inflammatory response, in conjunction with other secondary effector T cell functions, results in better control and more rapid resolution of both infection and the associated tissue pathology. Recent advancements in our understanding of inflammatory triggers, imprinting of the innate immune responses, and the role of T cell memory in regulating inflammation are discussed.

1. Introduction

Advances on several research fronts have significantly broadened our understanding of the triggers and modulators of inflammation. Of importance to this review, we now appreciate that at sites of infection, adaptive immune memory cells regulate innate inflammatory responses that contribute to the control of pathogens. Herein, potential means to modulate inflammation for the optimal generation of protective immunity through vaccination are discussed.

The ultimate goal of vaccination is to stimulate the generation of long-lived protective immunity without causing adverse clinical symptoms. Traditional vaccination strategies employing inactivated or attenuated pathogens or pathogen-derived protein antigens primarily target the generation of neutralizing antibody responses from B cells that act to prevent infection upon pathogen reencounter [1]. These regimes have been remarkably effective at mitigating the morbidity and mortality of a number of infectious diseases in vaccinated populations and most notably have led to the complete eradication of smallpox [2]. However, intracellular pathogens like influenza viruses (IAV) [3], human immunodeficiency virus (HIV) [4], and Mycobacterium tuberculosis [5, 6] have yet to be effectively controlled by neutralizing antibody-based vaccine approaches. Such pathogens either rapidly mutate external proteins that are targets for antibody or are not likely seen by antibody and are more effectively controlled by cell-mediated immune responses. The generation of protective T cell-mediated immunity through vaccination is appealing for pathogens like IAV that undergo antigenic shifts to evade neutralizing antibody given that T cells can recognize antigenic targets that are more conserved between strains. T cell-based vaccines against IAV may thus have the benefit of mediating universal protection against unforeseen and emergent pandemic strains of the virus [7], and they may potentially also eliminate the need for annual IAV vaccine reformulation. Inflammatory enhancing adjuvants have the potential to boost the efficacy of novel neutralizing antibody-based and T cell-based vaccines [8–11]. In order for such adjuvanated T cell-based vaccines to be efficacious and safe, they will need to target the induction of both pathogen-specific inflammation and adaptive immunity at relevant sites of infection.

2. There: The Regulation of Innate Inflammatory Responses by Pathogen

When a pathogen breaches the initial barriers of the skin or a mucosal surface, both soluble and cellular innate defense mechanisms are encountered and an inflammatory response is rapidly initiated. Some of the most potent soluble antimicrobial factors encountered include complement, lysozymes, defensins, mucins, lectins, cathelicidins, and lipocalins [12–15]. Several of these soluble antimicrobial mediators, such as activated complement components and lipocalin-2, are pluripotent, and in addition to performing antimicrobial functions, they amplify the inflammatory response triggered in resident sentinel immune cells upon pathogen sensing [13, 16, 17]. Within minutes to hours of detection of alarm signals, a “heightened alert” inflammatory transcriptional program ensues in sentinel innate immune cells, which include tissue-resident macrophages and dendritic cells. The result of this program is the generation of an antipathogen state and the production of a myriad of inflammatory cytokines, chemokines, biogenic amines, and eicosanoids [18] that induce a similar state in neighboring tissue cells.

Soluble inflammatory chemokines [19] and activated complement [20, 21] produced in response to pathogen sensing contribute to the attraction of additional innate immune cells such as neutrophils, NK cells, and monocytes to the site of infection [19, 22]. The recruited inflammatory cells encircle the damaged or infected cells and release more proinflammatory cytokines including tumor necrosis factor (TNF), IL-6, IL-12, and type I and II interferons (IFNs). Neutrophils also release DNA nets to trap free extracellular pathogens [23, 24], and NK cells attempt to lyse infected host cells through cytotoxic means [25, 26]. The innate inflammatory cytokine and cellular swarm attempts to contain the pathogen until highly specific, activated cells of the adaptive immune response are recruited to ultimately clear the infection [27]. If coordinated recruitment of innate and adaptive immunity fails to effectively control the pathogen, clinical disease will ensue. A major challenge for vaccine design is to mimic this inflammatory environment, which is needed to stimulate the generation of effective and robust immunity, without causing the immunopathology and tissue damage associated with clinical infection.

2.1. Pathogen Sensing

In order for the inflammatory events discussed above to occur, pathogens must be detected in compromised tissues. Many different subsets of classic dendritic cells, plasmacytoid dendritic cells, and macrophages [28, 29] are distributed throughout tissues in a network that facilitates immediate detection of both invading pathogens and the associated tissue damage [30, 31]. These sentinel innate cells sense pathogens and pathogen-associated tissue damage in a generic way through multiple distinct pathways [32]. They employ germ-line encoded pattern recognition receptors (PRRs) that recognize pathogen-associated molecular pattern (PAMPs) [32] and damage-associated molecular pathogens (DAMP) [33, 34] to detect changes in their environment [35, 36]. Recognition of pathogen-derived products such as lipopolysaccharide (LPS) by Toll-like receptors (TLR) 1, 2, and 4; flaggelin by TLR5; single stranded (ss) by TLRs 7 and 8; double-stranded (ds) RNA by TLR 3; and CpG DNA by TLR9 occurs either at the surface of the cell or within endoplasmic vesicles [37]. Host cell-derived danger signals or alarmins such as heat shock proteins, uric acid crystals, high-mobility group box 1, S100 proteins, serum amyloid A, and products of purine metabolism released from damaged or stressed cells are sensed by DAMP receptors such as RAGE, TLRs, and purinergic receptors [38, 39]. Recognition of PAMPs and DAMPs triggers the activation of signaling pathways that ultimately leads to the expression of the transcription factors NF-κb, AP-1, and interferon regulatory factors (IRFs) [32, 40, 41]. These transcription factors control the expression of hundreds of immune defense response genes [18, 40, 42]. An attractive means to both tailor and enhance the generation of vaccine-induced immunity is through the use of adjuvants that selectively trigger PRR and DAMP receptors. Such adjuvants are currently being explored to improve the generation of adaptive immune responses to inactivated pathogen and protein-based vaccines [8–11].

Advancements in our knowledge of intracellular sensors of pathogens and host-derived stress products have revealed novel targets to modulate and improve vaccine efficacy [43, 44]. A number of intracellular sensors, including the nucleotide-binding-domain and leucine-rich-repeat- (NLR-) containing proteins [45, 46] and the AIM-like-receptor (ALR) proteins [47], trigger the inflammasome pathway. The activation of the inflammasome complex and the activation of caspase-1 enzymatic activity are best known for triggering maturation of the proforms of the cytokines IL-1 and IL-18 [48]. However, alternative outcomes such as phagosome maturation, autophagy, glycolysis, lipid metabolism, and oxidation of arachidonic acid to generate eicosanoid signaling molecules, as well as inflammatory pyroptotic cell death, can also be triggered [44]. IL-1 and IL-18, in their mature forms, are potent proinflammatory cytokines [49]. The importance of the inflammasome-sensing pathway and the production of IL-1 and IL-18 to effective pathogen defense is highlighted by the fact that many infectious organisms, such as viruses, that gain access to the cytosol encode proteins that attempt to evade detection by intracellular sensors [50].

Intracellular sensors interact with adaptor proteins such as apoptosis-associated speck-like protein containing a C-terminal caspase activation and recruitment domain (ASC) [51] to trigger the activation of the proteolytic functions of the caspase-1 enzyme. Triggers of caspase enzymatic activity are extensively reviewed elsewhere [44, 46, 52]. The discovery of noncanonical activation pathways involving caspases other than caspase-1 [44, 53], as well as the ability of the type I IFN, a pro- and anti-inflammatory cytokine [54], to both prime cells for cytosolic sensing [44] and inhibit NLR signaling [55] emphasizes the need to more fully understand the workings of the inflammasome complex before targeted modulators [56] can be employed to enhance the generation of vaccine-induced memory CD4 and CD8 T cell immune responses.

2.2. Inflammatory “Rheostats”

Under normal circumstances, inhibitory “innate immune rheostats” act to prevent unnecessary inflammation at barrier surfaces [57, 58]. Inflammatory responses in tissues are tempered in many ways via recognition of soluble as well as cell surface ligands. This includes the blockade of activating DAMP receptor signaling by tissue-derived factors such as surfactant proteins and mucins [59–62]. Inhibitory DAMP receptor and inhibitory cytosolic receptor triggering by host-derived ligands such as DNA is an additional example of how inflammatory responses are kept in check [63–65]. Ligation of cell surface receptors on monocytes and dendritic cells, such as CD200R by CD200 ligand, that trigger dampening signals [66] is yet an additional means by which inflammation is regulated. Lastly, suppression of NF-κb activation by the release of mitochondrial H₂O₂ in lung APC [67] and the production of the anti-inflammatory cytokines IL-10 and TGF-beta by both regulatory T cells and tissue cells [68–70] mitigate inflammatory responses. The potent efficiency of IL-10 and TGB-beta in counterregulating inflammatory cytokine production as well as in inhibiting both costimulatory and major histocompatibility complex (MHC) molecule expression on antigen-presenting cells (APCs) likely explains why many pathogenic viruses encode homologues of inhibitory cytokines and inhibitory ligands to evade the innate immune response. Expression of IL-10 by Epstein-Barr virus (EBV) [71] and expression of the inhibitory ligand CD200 by cytomegalovirus (CVM) [72] are prime examples.

Safely overcoming these “rheostats” by targeted blockade of inhibitory molecules or by employing novel adjuvant formulations that facilitate the generation of protective local immunity through vaccination without causing damaging adverse effects is of paramount importance [73–75]. Indeed, the generation of overzealous inflammatory responses following pathogen or adjuvant stimulation has the potential to cause severe inflammatory disease [34, 76]. Individuals who possess well-characterized genetic polymorphisms in numerous inflammatory mediators and signaling molecules, such as those associated with chronic inflammatory diseases like psoriasis, ulcerative colitis, and Crohn’s disease [77], are at increased risk for developing undesired inflammatory complications following vaccination. In addition to genetic predispositions, environmental factors, such as the microbiome, may also play a role in setting the inflammatory “rheostat” at mucosal surfaces [78–82]. Interestingly, individual-specific microbiota signatures have been shown to impact both disease susceptibility and severity via either innate or adaptive immune pathways [83].

The control of immune response gene expression by long noncoding (lnc) RNAs [84] is another recently described homeostatic mechanism that could be targeted to improve vaccine efficacy as well as for therapeutic control of inflammation. Depending on the cell type involved, binding of specific lnc RNAs to regulatory regions of immune response genes and the subsequent control of nucleosome positioning can either promote or actively repress inflammatory gene expression [85]. A number of long noncoding RNAs are dysregulated during viral infection [86, 87], and changes in their expression are being assessed for use as biomarkers of disease severity [88]. The control of inflammatory responses by noncoding RNAs could have an exciting future in tailoring host inflammatory responses.

In addition to the homeostatic mechanisms and negative feedback loops discussed above, which preserve vital functions of organs such as the lung and intestine, the timing of vaccination administration may also need to be taken into account. Patterns of expression of proteins such as IL-6, inflammatory monocyte chemokine ligand (CCL2), as well as Toll-like receptor (TLR) 9, which are regulated by circadian clock proteins [89], may explain why morning vaccine administration appears more effective than afternoon administration at inducing specific antibody in older adults [90]. Differences in the magnitude of inflammatory responses across seasons may also influence the efficacy of vaccination. A recent study found that the magnitude of the inflammatory cytokine response detected following stimulation of monocytes with different pathogen-derived products, including those from influenza A virus, differs in different seasons [91]. In the individuals studied, inflammatory cytokine responses were maximal during the summer months of June and July and weakest in winter months [91]. The authors speculate that the tendency to produce reduced levels of inflammatory cytokines such as IL-1, TNF, and IL-6 during the winter may impact an individual’s susceptibility to pathogens such as influenza A during the flu season. How the efficiency of vaccination is affected by the seasonal changes warrants further investigation.

3. Inflammation and the Generation of Adaptive Immune Responses

To successfully generate protective immunity through vaccination, antigen-specific T cells must interact with activated APC displaying cognate antigen in the context of MHC. Such interactions result in the receipt of signal 1, the specific antigen, and signal 2, the costimulatory molecule-dependent signals, required for full T cell activation. Recognition of inflammatory cytokines by their corresponding cytokine receptors constitutes signal 3 that can amplify proliferation as well as effector functions in activated cells.

Foreign antigens introduced by vaccination must reach the secondary lymphoid organs in order for T cell activation to occur. Antigen is delivered to draining lymph nodes via the lymph in particulate form or within migrating tissue-resident antigen-presenting cells that have egressed from the inflammatory site [92]. Particulate antigens in the lymph are captured by specialized APCs that are strategically poised in the draining lymph nodes [93]. Larger-sized antigens are captured by lymph node dendritic cells that reside within the lymphatic sinus endothelium [93] or by subcapsular sinus macrophages [94, 95]. Smaller-sized antigens are transferred to lymph node follicle dendritic cells and B cells via a conduit system [96]. Once engulfed and processed, antigens are presented by antigen-presenting macrophages, dendritic cells, and/or B cells to naïve CD4 and CD8 T cells on MHC class II and class I molecules, respectively. Antigens that gain access to the circulation are delivered to the spleen via the blood and are detected in a similar fashion by the APCs that reside there.

Exposure to and engulfment of pathogen-derived products at the site of vaccination or infection activates APCs and triggers their production of inflammatory cytokines. Cohorts of APC, once activated, will begin to migrate towards lymphoid organ chemokines CCL19 and CCL21 in a CCR7-dependent fashion [97, 98]. Egress of tissue-resident APC from sites of infection is a rapid event, and migratory subsets can be detected in lymphoid organs within 14 to 24 hrs of antigen administration [99, 100]. Both tissue-resident dendritic cells and macrophages display migratory behavior upon activation [29, 101–103]. Interestingly, following infection with respiratory viruses such as influenza A virus, one APC subset, alveolar macrophages, becomes undetectable in the infected lung tissue until recruited monocytes are able reestablish the population [104]. It remains unclear, however, whether the inability to detect alveolar macrophages following influenza is the result of their complete egress out of the tissue, a switch in their surface marker phenotype in response to the inflammatory milieu, or because of their elimination by the viral infection [29, 102].

The lifespan of activated tissue-migratory APCs within draining lymph nodes, especially the dendritic cell subset, is relatively short [105], and optimal antigen presentation by such cells occurs within 24 hrs of tissue egress [99, 100]. In addition to functioning as APCs within the T cell zones [101, 106], migratory dendritic cells can also act as “cargo carriers” that deliver engulfed antigen to APC resident in lymphoid organs [107, 108]. Whether migratory or lymph node resident, APCs once activated express increased levels of MHC I and II molecules, as well as increased expression of costimulatory molecules, such as CD40, CD70, CD80, and CD86 [28]. Activated APCs also produce numerous proinflammatory cytokines including IL-12, IL-6, and type I IFN for the plasmacytoid dendritic cell subset [28]. The inflammatory mediators that these highly activated APCs produce and the surface costimulatory molecules that they express play a key role in shaping the ensuing adaptive immune response [109, 110]. Vaccine strategies that specifically target pathogen-derived antigens to APCs in vivo [111], that employ antigen-loaded dendritic cells themselves as the vaccine vehicles [112], or that additionally trigger specific PRR receptors to direct T cell polarization are actively being explored as means to amplify the generation of effective T cell responses [8–10]. Such strategies are of particular interest for vaccination regimes for the elderly and cancer patients where the generation of effective immunity is challenging because of their compromised or suppressed immune states [112, 113].

3.1. And Back Again: The Regulation of Early Innate Inflammatory Responses by Memory T Cells

Following an acute infection or vaccination, the activation and expansion of naïve pathogen-specific T cells and the generation of effector cells generally occur within 7 days. Under normal circumstances, the majority of expanded effector cells that migrate to sites of infection or antigen administration undergo contraction following subsequent pathogen or antigen clearance. A small cohort of the expanded effectors will, however, survive to memory [114]. These antigen-specific memory cells, which exist at a frequency higher than that found in the naïve state [115], mediate potent immunological protection upon secondary pathogen encounter.

Some antigen-specific memory T cells possess the ability to migrate throughout the body and are readily detected within tissues [116, 117]. This migration pattern is markedly different from that of naïve T cells, which only circulate through the blood and secondary lymphoid tissues [118, 119]. When compared to naïve T cells, memory T cells also have increased cytokine-producing potential [120, 121]. One subset of memory T cells, the tissue-resident memory T cell subset that does not circulate, is found exclusively within the tissues and may be strategically poised and specialized to perform sentinel functions [122–125]. Targeting the generation of tissue-resident memory T cells, especially for pathogens that infect mucosal tissues, is thus an attractive means to improve the efficacy of vaccines against pathogens that are not effectively controlled by traditional antibody-based approaches.

In addition to rapidly producing cytokines upon recognition of cognate antigen, memory T cells perform many other effector functions to protect the host against infection [126]. These functions are, for the most part, recalled independently of most costimulatory molecules [127]. This is one major way in which memory cells are distinct from naïve T cells that are dependent upon costimulatory signals for their full activation. For CD4 T cells, the best-known effector role is the provision of help for antigen-specific B [128] and cytotoxic CD8 T cell responses as reviewed elsewhere [126, 129, 130]. A novel effector role of memory T cells that is becoming more appreciated is the regulation of innate immune responses at sites of infection [126]. Of importance to this discussion, memory T cells mediate rapid production of effector cytokines akin to the responses elicited from innate immune cells upon cognate encounter with specific pathogen-derived antigen. Memory T cells thus have the potential to act as powerful antigen-specific sentinels that are able to initiate rapid inflammatory responses against pathogens [122, 131–133]. In fact, our studies in an influenza model showed that memory T cell-mediated inflammatory responses are induced faster, are bigger, and are better at containing virus than innate responses in naïve IAV-infected animals that are triggered through PRR-dependent mechanisms [133] (Figure 1).

Figure 1: Memory T cells regulate inflammation at sites of infection. Traditional paradigms of innate instruction of adaptive immunity must now also appreciate that adaptive memory T cells regulate both the nature and shape of innate inflammatory responses. Memory CD4 T cell-mediated enhanced inflammatory responses are initiated independently of the classic PRR signaling and classic costimulatory molecule recognition and are better at containing virus than innate responses triggered in naïve hosts through PAMP-dependent mechanisms.

Both memory CD4 [132, 133] and CD8 [131, 134, 135] T cells have the capacity to regulate and enhance the generation of early innate inflammatory responses within tissues upon cognate recognition of antigen. The antigen-specific regulation of inflammatory responses provides an additional means by which the immune response can generate alarm signals during infections with pathogens that possess means to evade detection by the innate immune-sensing mechanisms discussed earlier [136]. It also provides a means whereby experienced memory cells can modulate the effector functions of the ensuing adaptive response of expanded secondary effector T cells that arise from resting memory T cell precursors during recall [137].

For memory CD4 T cells, enhanced inflammatory responses are initiated in the lung following IAV infection independently of the classic PRR signaling molecules MYD88 and TRIF [133]. Memory CD4 T cell-regulated enhanced inflammatory responses can also be initiated in the absence of infection. Indeed, the intranasal administration of cognate peptide antigen in the absence of any adjuvants or the administration of endotoxin-free protein that contains the epitope for which the cells are specific leads to the generation of potent early innate inflammatory responses [133]. This suggests that even though CD4 T cells themselves can express PRRs and produce inflammatory cytokines following PAMP recognition [138, 139], such PRR triggering is not required for the mediation of memory CD4 T cell sentinel functions [133].

The ability of memory CD4 T cells to induce inflammatory responses upon pathogen detection is also independent of their production of the classic proinflammatory cytokines TNF and IFN-γ and does not require the receipt of CD80, CD86, and CD40 costimulatory molecule signals [133]. That memory cells do not depend on signal 2 to perform sentinel functions within the lung is in fitting with the observation that the activation and early recall of memory CD4 T cells in vivo are not affected by blockade of the CD28 costimulatory pathway [140]. The sentinel capacity of memory CD4 T cells thus appears to be very different from the sentinel functions of CD8 T cells, which are dependent upon TNF [141], IFN-γ [142–144], GM-CSF [145], and potentially also the receipt of costimulatory signals in vivo [146]. Similarities and inherent differences in the priming and function of memory CD4 and CD8 T cell responses are additional factors that must be considered in the design of innovative vaccination strategies that target the generation of protective antigen-specific T cells.

Following secondary IAV infection, the earlier and more robust inflammatory response induced by memory CD4 T cells correlates with improved control of the virus in the lung [133]. Our recent findings show that one innate inflammatory cytokine involved in this response, IL-6, plays a central role in maximizing the multicytokine-producing potential of secondary CD4⁺ T effector cells that accumulate in the lung at the peak of the recall response [137] (Figure 2). In murine and human systems, multicytokine-producing potential, or the ability to coproduce TNF, IL-2, and IFN-γ, is associated with the ability of memory T cell responses to protect against numerous viral, bacterial, and parasitic pathogens [120]. Multicytokine potential, as well as the ability to mediate effector functions such as help and cytotoxicity, correlates with superior protective capacity when secondary effector cells (derived from memory precursors) are compared on a per cell basis to primary effectors derived from naïve T cells [121, 147, 148]. Innovative vaccines thus not only should target the induction of large numbers of memory T cells but also should strive to generate cells that possess optimal functional potential. Current research employing high-dimensional mass cytometry that simultaneously measures over 40 parameters, including cell surface markers and intracellular proteins, as well as RNA expression at single-cell resolution [149], will further advance our understanding of strong correlates of protection in specific models of infection. Such correlates will, in turn, help facilitate the development of optimal vaccination strategies.

Figure 2: Memory T cells regulate the accumulation and functional potential of secondary effector T cells in the lung through antigen-specific upregulation of the inflammatory cytokine IL-6. Following secondary IAV infection, the earlier and more robust inflammatory response induced by memory CD4 T cells correlates with improved control of the virus in the lung. One innate inflammatory cytokine involved in this response, IL-6, plays a central role in maximizing the multicytokine-producing potential of secondary CD4⁺ T effector cells that accumulate in the lung at the peak of the recall response. Experienced memory cells thus modulate the effector functions of recently expanded secondary effector T cells that arise from resting memory T cell precursors during recall responses by inducing potent inflammatory signals.

4. Training of the Innate Immune System

Another significant advance in our understanding of innate immunity is the knowledge that cells of the innate immune system are altered or “trained” by past experiences [150]. For the majority of innate immune cells, such imprinting results in a generic and nonspecific heightened inflammatory response that increases host antimicrobial defenses upon secondary infection. Responses by NK cells may be an exception to this as they have been shown to display some elements of antigen-dependent memory [151–153]. It should be noted, however, that trained innate immune responses are functionally distinct from the highly specific recall responses characteristic of adaptive immune memory mediated by specialized subsets of CD4 and CD8 T cells and of antibody-producing B cells.

It has been long been appreciated that organs such as the lung remain in an altered state for an extended period of time following infection or insult [154, 155]. The heightened inflammatory state that exists following the resolution of pathogen infection lasts for days, weeks, or even months and can provide a degree of nonspecific protection to unrelated pathogens. Examples of heightened protective immunity induced by infection or vaccination are many and are discussed in detail elsewhere [150, 156, 157]. A prime example is the ability of BCG vaccination, in mice as well as in humans, to increase resistance against a number of different pathogens [157–160]. Priming of innate immune cells resulting in increased nonspecific pathogen protection can also be caused by viral pathogens [161, 162] and even exposure to pathogen-derived molecular patterns [163–166].

The protection afforded by “imprinted” innate immunity is associated with the presence of increased numbers of activated macrophages [150, 156], dendritic cells [167], and other innate immune cells within the tissues that are characterized as being in a heightened antimicrobial state [150, 156]. In animal models, this nonspecific protection is transferrable to naïve hosts by the adoptive transfer of “trained” macrophages, and, notably, the transfer of protection does not require the presence of T cells [165, 168]. Recent studies have shown that this “imprinted” state is maintained by long-term translational and epigenetic changes within the “trained” monocytes and macrophages [165, 169, 170]. Signals generated through recognition of the microbiota that ultimately lead to the production of the inflammatory cytokine GM-CSF, which also has colony-stimulating functions, is just one example of how heightened inflammatory “rheostats” can be established within mucosal tissues [171]. How conditioning of innate immune cells by the microbiota and infectious pathogens in human tissues influences the ability to generate protective immune responses following vaccination remains to be determined. However, some groups have begun to establish models using primary human monocytes to shed preclinical insight on the ability of pathogen-derived products to “imprint” human APC in vitro [172].

Pathogen-associated encounters may not be the only events capable of training innate immune cells. The engulfment of apoptotic host cells in the absence of infection has traditionally been considered an immunologically neutral event that fails to generate DAMP signals [33]. Recent observations, however, show that even this steady-state process can imprint macrophages for heightened inflammatory responses that mediate nonspecific resistance to microbial infection [173]. These and other findings in a murine model [174] suggest that most if not all tissue-resident macrophages become experienced during development by normal cellular turnover processes that educate them for future pathogen encounter.

The altered inflammatory state that exists following the resolution of infection can also have alternative and undesired outcomes. For example, conditioning of innate immune cells by prior infection can result in increased susceptibility to secondary infection [175]. Increased susceptibility to secondary bacterial infection occurs following many respiratory virus infections [176] and contributes markedly to the morbidity and mortality of disease [177]. Mechanisms underlying increased susceptibility to secondary infection are many and include deficiencies in bacterial scavenging receptors such as MARCO on macrophages [178], as well as the depletion of tissue-resident APC populations during primary infection [104]. Increased production of inflammatory dampening cytokines IL-10 and TGF-beta [179, 180] and attenuation of protective host defenses through diminished production of IL-1b [181], IL-27 [182], and antimicrobial peptides [181] can also contribute to increased susceptibility. Increased expression of inflammatory dampening receptors such as CD200R [66, 155] and differences in the chemotaxis, survival, phagocytic, and respiratory burst functions of neutrophils [183–185] may also lead to an inability of the innate immune system to contain and control secondary microbial threats following respiratory viral infection. In addition to regulating early inflammatory responses that facilitate pathogen control, vaccine-induced T cell immunity may also be able to prevent these deficiencies in innate immunity as experimental evidence suggests that susceptibility to secondary bacterial infections is mitigated in primed animals in models of IAV infection [186].

4.1. And Back Yet Again: Heterologous Infection, Memory T Cells, and Inflammation

While highly specific in nature, the adaptive immune response can also alter the outcome of infections with seemingly unrelated pathogens. This phenomenon, which has been termed heterologous immunity [187], is mediated by cross-reactive T cells with T cell receptors that have the potential to recognize more than one peptide-MHC complex. Heterologous immunity is long-lasting and much like “innate imprinting” it can be either beneficial or detrimental. For instance, in animal models of lymphocytic choriomeningitis virus (LCMV), cytomegalovirus (CMV), or IAV infection, prior virus-specific immunity has a beneficial impact on the outcome of subsequent vaccinia virus infection and results in improved viral clearance [188]. However, in the reverse scenario, prior IAV-specific immunity can increase the immunopathology of respiratory LCMV and murine CMV infection. Preexisting, heterologous immunity has been shown to alter protective T cell immunodominance hierarchies induced by primary infection. It is argued that the presence of cross-reactive T cells narrows the virus-specific T cell repertoire and drives the selection of viruses able to escape adaptive immunity. Conversely, the recall of cross-reactive memory T cells can also result in protective immune responses. Given the capacity of memory T cells to regulate inflammation [133, 135], beneficial heterologous immunity in the latter scenario likely also involves well-guided innate inflammatory responses that contribute to the initial control of pathogens. One can thus infer from these studies that the severity of disease is impacted not only by the past history of infections but also by the sequence of such infections. These observations have important implications for the design and timing of the delivery of vaccines [189].

5. Summary

Understanding of the impact of prior pathogen encounter on both innate and adaptive immunity is imperative for the design of innovative vaccination regimes. Exciting developments in the field of macrophage and monocyte biology are changing the way memory is typically perceived in innate immune cells. The “training” of innate immunity must be further investigated in order to effectively implement these insights into improved vaccines that are better able to promote durable memory states. In addition, traditional paradigms of innate instruction of adaptive immunity must now appreciate that memory T cells regulate both the nature and shape of innate inflammatory responses through antigen-specific means. Furthermore, memory-regulated inflammatory responses can impact the development and functional potential of secondary effector T cells. Every infection, commensal interaction, and immunogenic vaccine thus has the potential to change the host tissue microenvironment as well as the adaptive immune T cell repertoire. Such changes can impart lasting immunological consequences that are able to influence subsequent responses to infection both positively and negatively.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Acknowledgments

The authors thank Dr. Karl Kai McKinstry for his critical review of the manuscript. This work was supported by funds to Tara M. Strutt from NIH R21 Grant no. AI117457-01A1, the State of Florida Crohn’s Funding Appropriation, and the University of Central Florida College of Medicine, Burnett School of Biomedical Sciences. David Alex Cronkite received support from the University of Central Florida College of Medicine Focused Inquiry and Research Experience Program.

References

M. K. Slifka and I. Amanna, “How advances in immunology provide insight into improving vaccine efficacy,” Vaccine, vol. 32, no. 25, pp. 2948–2957, 2014.

R. A. Weiss and J. Esparza, “The prevention and eradication of smallpox: a commentary on Sloane (1755) ‘An account of inoculation’,” Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences, vol. 370, no. 1666, 2015.

P. G. Thomas, R. Keating, D. J. Hulse-Post, and P. C. Doherty, “Cell-mediated protection in influenza infection,” Emerging Infectious Diseases, vol. 12, no. 1, pp. 48–54, 2006.

D. H. Barouch and S. G. Deeks, “Immunologic strategies for HIV-1 remission and eradication,” Science, vol. 345, no. 6193, pp. 169–174, 2014.

S. M. Behar, “Antigen-specific CD8⁺ T cells and protective immunity to tuberculosis,” Advances in Experimental Medicine and Biology, vol. 783, pp. 141–163, 2013.

C. S. Lindestam Arlehamn, D. Lewinsohn, A. Sette, and D. Lewinsohn, “Antigens for CD4 and CD8 T cells in tuberculosis,” Cold Spring Harbor Perspectives in Medicine, vol. 4, no. 7, article a018465, 2014.

S. Sridhar, “Heterosubtypic T-cell immunity to influenza in humans: challenges for universal T-cell influenza vaccines,” Frontiers in Immunology, vol. 7, p. 195, 2016.

B. Guy, “The perfect mix: recent progress in adjuvant research,” Nature Reviews Microbiology, vol. 5, no. 7, pp. 505–517, 2007.

R. L. Coffman, A. Sher, and R. A. Seder, “Vaccine adjuvants: putting innate immunity to work,” Immunity, vol. 33, no. 4, pp. 492–503, 2010.

A. Gutjahr, G. Tiraby, E. Perouzel, B. Verrier, and S. Paul, “Triggering intracellular receptors for vaccine adjuvantation,” Trends in Immunology, vol. 37, no. 9, pp. 573–587, 2016.

K. Kastenmüller, U. Wille-Reece, R. W. B. Lindsay et al., “Protective T cell immunity in mice following protein-TLR7/8 agonist-conjugate immunization requires aggregation, type I IFN, and multiple DC subsets,” The Journal of Clinical Investigation, vol. 121, no. 5, pp. 1782–1796, 2011.

S. S. Wilson, M. E. Wiens, M. K. Holly, and J. G. Smith, “Defensins at the mucosal surface: latest insights into defensin-virus interactions,” Journal of Virology, vol. 90, no. 11, pp. 5216–5218, 2016.

A. R. Moschen, T. E. Adolph, R. R. Gerner, V. Wieser, and H. Tilg, “Lipocalin-2: a master mediator of intestinal and metabolic inflammation,” Trends in Endocrinology and Metabolism, vol. 28, no. 5, pp. 388–397, 2017.

J. M. Ageitos, A. Sanchez-Perez, P. Calo-Mata, and T. G. Villa, “Antimicrobial peptides (AMPs): ancient compounds that represent novel weapons in the fight against bacteria,” Biochemical Pharmacology, vol. 133, pp. 117–138, 2017.

P. Chairatana and E. M. Nolan, “Defensins, lectins, mucins, and secretory immunoglobulin a: microbe-binding biomolecules that contribute to mucosal immunity in the human gut,” Critical Reviews in Biochemistry and Molecular Biology, vol. 52, no. 1, pp. 45–56, 2017.

G. Hajishengallis, E. S. Reis, D. C. Mastellos, D. Ricklin, and J. D. Lambris, “Novel mechanisms and functions of complement,” Nature Immunology, vol. 18, no. 12, pp. 1288–1298, 2017.

C. S. Hau, N. Kanda, Y. Tada et al., “Lipocalin-2 exacerbates psoriasiform skin inflammation by augmenting T-helper 17 response,” The Journal of Dermatology, vol. 43, no. 7, pp. 785–794, 2016.

I. Amit, M. Garber, N. Chevrier et al., “Unbiased reconstruction of a mammalian transcriptional network mediating pathogen responses,” Science, vol. 326, no. 5950, pp. 257–263, 2009.

S. J. Kang, H. E. Liang, B. Reizis, and R. M. Locksley, “Regulation of hierarchical clustering and activation of innate immune cells by dendritic cells,” Immunity, vol. 29, no. 5, pp. 819–833, 2008.

G. Castellano, A. M. Woltman, F. P. Schena, A. Roos, M. R. Daha, and C. van Kooten, “Dendritic cells and complement: at the cross road of innate and adaptive immunity,” Molecular Immunology, vol. 41, no. 2-3, pp. 133–140, 2004.

B. P. Morgan and P. Gasque, “Extrahepatic complement biosynthesis: where, when and why?” Clinical and Experimental Immunology, vol. 107, no. 1, pp. 1–7, 1997.

T. Lämmermann, P. V. Afonso, B. R. Angermann et al., “Neutrophil swarms require LTB4 and integrins at sites of cell death in vivo,” Nature, vol. 498, no. 7454, pp. 371–375, 2013.

C. N. Jenne, C. H. Y. Wong, F. J. Zemp et al., “Neutrophils recruited to sites of infection protect from virus challenge by releasing neutrophil extracellular traps,” Cell Host & Microbe, vol. 13, no. 2, pp. 169–180, 2013.

V. Brinkmann, U. Reichard, C. Goosmann et al., “Neutrophil extracellular traps kill bacteria,” Science, vol. 303, no. 5663, pp. 1532–1535, 2004.

H. Spits, J. H. Bernink, and L. Lanier, “NK cells and type 1 innate lymphoid cells: partners in host defense,” Nature Immunology, vol. 17, no. 7, pp. 758–764, 2016.

R. M. Welsh Jr., “Cytotoxic cells induced during lymphocytic choriomeningitis virus infection of mice. I. Characterization of natural killer cell induction,” Journal of Experimental Medicine, vol. 148, no. 1, pp. 163–181, 1978.

A. Rivera, M. C. Siracusa, G. S. Yap, and W. C. Gause, “Innate cell communication kick-starts pathogen-specific immunity,” Nature Immunology, vol. 17, no. 4, pp. 356–363, 2016.

M. Merad, P. Sathe, J. Helft, J. Miller, and A. Mortha, “The dendritic cell lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting,” Annual Review of Immunology, vol. 31, no. 1, pp. 563–604, 2013.

M. Guilliams, B. N. Lambrecht, and H. Hammad, “Division of labor between lung dendritic cells and macrophages in the defense against pulmonary infections,” Mucosal Immunology, vol. 6, no. 3, pp. 464–473, 2013.

W. R. Heath and F. R. Carbone, “The skin-resident and migratory immune system in steady state and memory: innate lymphocytes, dendritic cells and T cells,” Nature Immunology, vol. 14, no. 10, pp. 978–985, 2013.

K. Neyt and B. N. Lambrecht, “The role of lung dendritic cell subsets in immunity to respiratory viruses,” Immunological Reviews, vol. 255, no. 1, pp. 57–67, 2013.

A. Iwasaki and R. Medzhitov, “Control of adaptive immunity by the innate immune system,” Nature Immunology, vol. 16, no. 4, pp. 343–353, 2015.

H. Kono and K. L. Rock, “How dying cells alert the immune system to danger,” Nature Reviews Immunology, vol. 8, no. 4, pp. 279–289, 2008.

G. Y. Chen and G. Nunez, “Sterile inflammation: sensing and reacting to damage,” Nature Reviews Immunology, vol. 10, no. 12, pp. 826–837, 2010.

C. A. Janeway Jr., “Approaching the asymptote? Evolution and revolution in immunology,” Cold Spring Harbor Symposia on Quantitative Biology, vol. 54, pp. 1–13, 1989.

P. Matzinger, “Tolerance, danger, and the extended family,” Annual Review of Immunology, vol. 12, no. 1, pp. 991–1045, 1994.

O. Takeuchi and S. Akira, “Pattern recognition receptors and inflammation,” Cell, vol. 140, no. 6, pp. 805–820, 2010.

D. V. Krysko, A. D. Garg, A. Kaczmarek, O. Krysko, P. Agostinis, and P. Vandenabeele, “Immunogenic cell death and DAMPs in cancer therapy,” Nature Reviews Cancer, vol. 12, no. 12, pp. 860–875, 2012.

A. D. Garg, L. Galluzzi, L. Apetoh et al., “Molecular and translational classifications of DAMPs in immunogenic cell death,” Frontiers in Immunology, vol. 6, p. 588, 2015.

A. J. Tong, X. Liu, B. J. Thomas et al., “A stringent systems approach uncovers gene-specific mechanisms regulating inflammation,” Cell, vol. 165, no. 1, pp. 165–179, 2016.

K. Honda and T. Taniguchi, “IRFs: master regulators of signalling by Toll-like receptors and cytosolic pattern-recognition receptors,” Nature Reviews Immunology, vol. 6, no. 9, pp. 644–658, 2006.

S. A. Samarajiwa, S. Forster, K. Auchettl, and P. J. Hertzog, “INTERFEROME: the database of interferon regulated genes,” Nucleic Acids Research, vol. 37, Supplement 1, pp. D852–D857, 2009.

F. Martinon, K. Burns, and J. Tschopp, “The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-β,” Molecular Cell, vol. 10, no. 2, pp. 417–426, 2002.

V. A. K. Rathinam and K. A. Fitzgerald, “Inflammasome complexes: emerging mechanisms and effector functions,” Cell, vol. 165, no. 4, pp. 792–800, 2016.

I. C. Allen, M. A. Scull, C. B. Moore et al., “The NLRP3 inflammasome mediates in vivo innate immunity to influenza A virus through recognition of viral RNA,” Immunity, vol. 30, no. 4, pp. 556–565, 2009.

J. von Moltke, J. S. Ayres, E. M. Kofoed, J. Chavarria-Smith, and R. E. Vance, “Recognition of bacteria by inflammasomes,” Annual Review of Immunology, vol. 31, no. 1, pp. 73–106, 2013.

T. Fernandes-Alnemri, J. W. Yu, P. Datta, J. Wu, and E. S. Alnemri, “AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA,” Nature, vol. 458, no. 7237, pp. 509–513, 2009.

S. M. Man and T. D. Kanneganti, “Converging roles of caspases in inflammasome activation, cell death and innate immunity,” Nature Reviews Immunology, vol. 16, no. 1, pp. 7–21, 2016.

O. Gross, C. J. Thomas, G. Guarda, and J. Tschopp, “The inflammasome: an integrated view,” Immunological Reviews, vol. 243, no. 1, pp. 136–151, 2011.

C. Lupfer, A. Malik, and T. D. Kanneganti, “Inflammasome control of viral infection,” Current Opinion in Virology, vol. 12, pp. 38–46, 2015.

V. Hornung, A. Ablasser, M. Charrel-Dennis et al., “AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC,” Nature, vol. 458, no. 7237, pp. 514–518, 2009.

H. Wen, E. A. Miao, and J. P.-Y. Ting, “Mechanisms of NOD-like receptor-associated inflammasome activation,” Immunity, vol. 39, no. 3, pp. 432–441, 2013.

S. M. Man and T. D. Kanneganti, “Regulation of inflammasome activation,” Immunological Reviews, vol. 265, no. 1, pp. 6–21, 2015.

J. M. Gonzalez-Navajas, J. Lee, M. David, and E. Raz, “Immunomodulatory functions of type I interferons,” Nature Reviews Immunology, vol. 12, no. 2, pp. 125–135, 2012.

G. Guarda, M. Braun, F. Staehli et al., “Type I interferon inhibits interleukin-1 production and inflammasome activation,” Immunity, vol. 34, no. 2, pp. 213–223, 2011.

C. Lupfer and T. D. Kanneganti, “Unsolved mysteries in NLR biology,” Frontiers in Immunology, vol. 4, p. 285, 2013.

H. Hammad and B. N. Lambrecht, “Barrier epithelial cells and the control of type 2 immunity,” Immunity, vol. 43, no. 1, pp. 29–40, 2015.

E. Wissinger, J. Goulding, and T. Hussell, “Immune homeostasis in the respiratory tract and its impact on heterologous infection,” Seminars in Immunology, vol. 21, no. 3, pp. 147–155, 2009.

H. A. Nguyen, M. V. S. Rajaram, D. A. Meyer, and L. S. Schlesinger, “Pulmonary surfactant protein A and surfactant lipids upregulate IRAK-M, a negative regulator of TLR-mediated inflammation in human macrophages,” American Journal of Physiology. Lung Cellular and Molecular Physiology, vol. 303, no. 7, pp. L608–L616, 2012.

S. W. Glasser, M. D. Maxfield, T. L. Ruetschilling et al., “Persistence of LPS-induced lung inflammation in surfactant protein-C-deficient mice,” American Journal of Respiratory Cell and Molecular Biology, vol. 49, no. 5, pp. 845–854, 2013.

K. Ueno, T. Koga, K. Kato et al., “MUC1 mucin is a negative regulator of toll-like receptor signaling,” American Journal of Respiratory Cell and Molecular Biology, vol. 38, no. 3, pp. 263–268, 2008.

Y. Kyo, K. Kato, Y. S. Park et al., “Antiinflammatory role of MUC1 mucin during infection with nontypeable Haemophilus influenzae,” American Journal of Respiratory Cell and Molecular Biology, vol. 46, no. 2, pp. 149–156, 2012.

S. Hangai, T. Ao, Y. Kimura et al., “PGE2 induced in and released by dying cells functions as an inhibitory DAMP,” Proceedings of the National Academy of Sciences of the United States of America, vol. 113, no. 14, pp. 3844–3849, 2016.

S. A. Schattgen, G. Gao, E. A. Kurt-Jones, and K. A. Fitzgerald, “Cutting edge: DNA in the lung microenvironment during influenza virus infection tempers inflammation by engaging the DNA sensor AIM2,” Journal of Immunology, vol. 196, no. 1, pp. 29–33, 2016.

S. Coutermarsh-Ott, K. Eden, and I. C. Allen, “Beyond the inflammasome: regulatory NOD-like receptor modulation of the host immune response following virus exposure,” Journal of General Virology, vol. 97, no. 4, pp. 825–838, 2016.

R. J. Snelgrove, J. Goulding, A. M. Didierlaurent et al., “A critical function for CD200 in lung immune homeostasis and the severity of influenza infection,” Nature Immunology, vol. 9, no. 9, pp. 1074–1083, 2008.

A. Khare, M. Raundhal, K. Chakraborty et al., “Mitochondrial H₂O₂ in lung antigen-presenting cells blocks NF-κB activation to prevent unwarranted immune activation,” Cell Reports, vol. 15, no. 8, pp. 1700–1714, 2016.

K. W. Moore, R. de Waal Malefyt, R. L. Coffman, and A. O'Garra, “Interleukin-10 and the interleukin-10 receptor,” Annual Review of Immunology, vol. 19, no. 1, pp. 683–765, 2001.

M. D. Roth and S. H. Golub, “Human pulmonary macrophages utilize prostaglandins and transforming growth factor β₁ to suppress lymphocyte activation,” Journal of Leukocyte Biology, vol. 53, no. 4, pp. 366–371, 1993.

E. M. Shevach and A. M. Thornton, “tTregs, pTregs, and iTregs: similarities and differences,” Immunological Reviews, vol. 259, no. 1, pp. 88–102, 2014.

K. W. Moore, P. Vieira, D. F. Fiorentino, M. L. Trounstine, T. A. Khan, and T. R. Mosmann, “Homology of cytokine synthesis inhibitory factor (IL-10) to the Epstein-Barr virus gene BCRFI,” Science, vol. 248, no. 4960, pp. 1230–1234, 1990.

G. Stack, E. Jones, M. Marsden et al., “CD200 receptor restriction of myeloid cell responses antagonizes antiviral immunity and facilitates cytomegalovirus persistence within mucosal tissue,” PLoS Pathogens, vol. 11, no. 2, article e1004641, 2015.

P. A. Darrah, S. T. Hegde, D. T. Patel et al., “IL-10 production differentially influences the magnitude, quality, and protective capacity of Th1 responses depending on the vaccine platform,” The Journal of Experimental Medicine, vol. 207, no. 7, pp. 1421–1433, 2010.

J. M. Pitt, E. Stavropoulos, P. S. Redford et al., “Blockade of IL-10 signaling during bacillus Calmette-Guérin vaccination enhances and sustains Th1, Th17, and innate lymphoid IFN-γ and IL-17 responses and increases protection to Mycobacterium tuberculosis infection,” The Journal of Immunology, vol. 189, no. 8, pp. 4079–4087, 2012.

S. Cusack and C. W. Muller, “Editorial overview: protein-nucleic acid interactions: an expanding universe,” Current Opinion in Structural Biology, vol. 47, pp. iv–iv, 2017.

M. Brandes, F. Klauschen, S. Kuchen, and R. N. Germain, “A systems analysis identifies a feedforward inflammatory circuit leading to lethal influenza infection,” Cell, vol. 154, no. 1, pp. 197–212, 2013.

E. Generali, A. Ceribelli, M. A. Stazi, and C. Selmi, “Lessons learned from twins in autoimmune and chronic inflammatory diseases,” Journal of Autoimmunity, vol. 83, pp. 51–61, 2017.

L. Wen, R. E. Ley, P. Y. Volchkov et al., “Innate immunity and intestinal microbiota in the development of type 1 diabetes,” Nature, vol. 455, no. 7216, pp. 1109–1113, 2008.

K. Cadwell, K. K. Patel, N. S. Maloney et al., “Virus-plus-susceptibility gene interaction determines Crohn’s disease gene Atg16L1 phenotypes in intestine,” Cell, vol. 141, no. 7, pp. 1135–1145, 2010.

C. Su, L. Su, Y. Li et al., “Helminth-induced alterations of the gut microbiota exacerbate bacterial colitis,” Mucosal Immunology, vol. 11, no. 1, pp. 144–157, 2017.

Q. Zhao, S. N. Harbour, R. Kolde et al., “Selective induction of homeostatic Th17 cells in the murine intestine by cholera toxin interacting with the microbiota,” Journal of Immunology, vol. 199, no. 1, pp. 312–322, 2017.

M. Schirmer, S. P. Smeekens, H. Vlamakis et al., “Linking the human gut microbiome to inflammatory cytokine production capacity,” Cell, vol. 167, no. 4, article e8, pp. 1125–1136.e8, 2016.

U. Roy, E. J. C. Galvez, A. Iljazovic et al., “Distinct microbial communities trigger colitis development upon intestinal barrier damage via innate or adaptive immune cells,” Cell Reports, vol. 21, no. 4, pp. 994–1008, 2017.

M. K. Atianand and K. A. Fitzgerald, “Long non-coding RNAs and control of gene expression in the immune system,” Trends in Molecular Medicine, vol. 20, no. 11, pp. 623–631, 2014.

M. K. Atianand, W. Hu, A. T. Satpathy et al., “A long noncoding RNA lincRNA-EPS acts as a transcriptional brake to restrain inflammation,” Cell, vol. 165, no. 7, pp. 1672–1685, 2016.

E. Carnero, M. Barriocanal, C. Prior et al., “Long noncoding RNA EGOT negatively affects the antiviral response and favors HCV replication,” EMBO Reports, vol. 17, no. 7, pp. 1013–1028, 2016.

E. R. Feldman, M. Kara, L. M. Oko et al., “A gammaherpesvirus noncoding RNA is essential for hematogenous dissemination and establishment of peripheral latency,” mSphere, vol. 1, no. 2, pp. e00105–e00115, 2016.

J. Ouyang, J. Hu, and J. L. Chen, “lncRNAs regulate the innate immune response to viral infection,” WIREs RNA, vol. 7, no. 1, pp. 129–143, 2016.

A. M. Curtis, M. M. Bellet, P. Sassone-Corsi, and L. A. J. O’Neill, “Circadian clock proteins and immunity,” Immunity, vol. 40, no. 2, pp. 178–186, 2014.

J. E. Long, M. T. Drayson, A. E. Taylor, K. M. Toellner, J. M. Lord, and A. C. Phillips, “Morning vaccination enhances antibody response over afternoon vaccination: a cluster-randomised trial,” Vaccine, vol. 34, no. 24, pp. 2679–2685, 2016.

R. ter Horst, M. Jaeger, S. P. Smeekens et al., “Host and environmental factors influencing individual human cytokine responses,” Cell, vol. 167, no. 4, pp. 1111–1124.e13, 2016.

R. N. Germain and M. K. Jenkins, “In vivo antigen presentation,” Current Opinion in Immunology, vol. 16, no. 1, pp. 120–125, 2004.

M. Y. Gerner, P. Torabi-Parizi, and R. N. Germain, “Strategically localized dendritic cells promote rapid T cell responses to lymph-borne particulate antigens,” Immunity, vol. 42, no. 1, pp. 172–185, 2015.

T. Junt, E. A. Moseman, M. Iannacone et al., “Subcapsular sinus macrophages in lymph nodes clear lymph-borne viruses and present them to antiviral B cells,” Nature, vol. 450, no. 7166, pp. 110–114, 2007.

T. G. Phan, J. A. Green, E. E. Gray, Y. Xu, and J. G. Cyster, “Immune complex relay by subcapsular sinus macrophages and noncognate B cells drives antibody affinity maturation,” Nature Immunology, vol. 10, no. 7, pp. 786–793, 2009.

R. Roozendaal, T. R. Mempel, L. A. Pitcher et al., “Conduits mediate transport of low-molecular-weight antigen to lymph node follicles,” Immunity, vol. 30, no. 2, pp. 264–276, 2009.

A. MartIn-Fontecha, S. Sebastiani, U. E. Hopken et al., “Regulation of dendritic cell migration to the draining lymph node: impact on T lymphocyte traffic and priming,” The Journal of Experimental Medicine, vol. 198, no. 4, pp. 615–621, 2003.

L. Ohl, M. Mohaupt, N. Czeloth et al., “CCR7 governs skin dendritic cell migration under inflammatory and steady-state conditions,” Immunity, vol. 21, no. 2, pp. 279–288, 2004.

A. A. Itano, S. J. McSorley, R. L. Reinhardt et al., “Distinct dendritic cell populations sequentially present antigen to CD4 T cells and stimulate different aspects of cell-mediated immunity,” Immunity, vol. 19, no. 1, pp. 47–57, 2003.

K. L. Legge and T. J. Braciale, “Accelerated migration of respiratory dendritic cells to the regional lymph nodes is limited to the early phase of pulmonary infection,” Immunity, vol. 18, no. 2, pp. 265–277, 2003.

A. Ballesteros-Tato, B. Leon, F. E. Lund, and T. D. Randall, “Temporal changes in dendritic cell subsets, cross-priming and costimulation via CD70 control CD8(+) T cell responses to influenza,” Nature Immunology, vol. 11, no. 3, pp. 216–224, 2010.

L. C. Davies, S. J. Jenkins, J. E. Allen, and P. R. Taylor, “Tissue-resident macrophages,” Nature Immunology, vol. 14, no. 10, pp. 986–995, 2013.

E. G. Perdiguero and F. Geissmann, “The development and maintenance of resident macrophages,” Nature Immunology, vol. 17, no. 1, pp. 2–8, 2016.

H. E. Ghoneim, P. G. Thomas, and J. A. McCullers, “Depletion of alveolar macrophages during influenza infection facilitates bacterial superinfections,” Journal of Immunology, vol. 191, no. 3, pp. 1250–1259, 2013.

A. T. Kamath, S. Henri, F. Battye, D. F. Tough, and K. Shortman, “Developmental kinetics and lifespan of dendritic cells in mouse lymphoid organs,” Blood, vol. 100, no. 5, pp. 1734–1741, 2002.

C. H. GeurtsvanKessel, M. A. M. Willart, L. S. van Rijt et al., “Clearance of influenza virus from the lung depends on migratory langerin⁺CD11b⁻ but not plasmacytoid dendritic cells,” The Journal of Experimental Medicine, vol. 205, no. 7, pp. 1621–1634, 2008.

G. T. Belz, C. M. Smith, L. Kleinert et al., “Distinct migrating and nonmigrating dendritic cell populations are involved in MHC class I-restricted antigen presentation after lung infection with virus,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 23, pp. 8670–8675, 2004.

H. Qi, J. G. Egen, A. Y. Huang, and R. N. Germain, “Extrafollicular activation of lymph node B cells by antigen-bearing dendritic cells,” Science, vol. 312, no. 5780, pp. 1672–1676, 2006.

A. Langenkamp, M. Messi, A. Lanzavecchia, and F. Sallusto, “Kinetics of dendritic cell activation: impact on priming of TH1, TH2 and nonpolarized T cells,” Nature Immunology, vol. 1, no. 4, pp. 311–316, 2000.

B. Pulendran, K. Palucka, and J. Banchereau, “Sensing pathogens and tuning immune responses,” Science, vol. 293, no. 5528, pp. 253–256, 2001.

R. M. Steinman, “Decisions about dendritic cells: past, present, and future,” Annual Review of Immunology, vol. 30, no. 1, pp. 1–22, 2012.

K. Palucka and J. Banchereau, “Dendritic-cell-based therapeutic cancer vaccines,” Immunity, vol. 39, no. 1, pp. 38–48, 2013.

J. E. McElhaney, G. A. Kuchel, X. Zhou, S. L. Swain, and L. Haynes, “T-cell immunity to influenza in older adults: a pathophysiological framework for development of more effective vaccines,” Frontiers in Immunology, vol. 7, p. 41, 2016.

K. K. McKinstry, T. M. Strutt, and S. L. Swain, “Regulation of CD4⁺ T-cell contraction during pathogen challenge,” Immunological Reviews, vol. 236, no. 1, pp. 110–124, 2010.

S. M. Kaech, E. J. Wherry, and R. Ahmed, “Effector and memory T-cell differentiation: implications for vaccine development,” Nature Reviews Immunology, vol. 2, no. 4, pp. 251–262, 2002.

R. L. Reinhardt, A. Khoruts, R. Merica, T. Zell, and M. K. Jenkins, “Visualizing the generation of memory CD4 T cells in the whole body,” Nature, vol. 410, no. 6824, pp. 101–105, 2001.

D. Masopust, V. Vezys, A. L. Marzo, and L. Lefrancois, “Preferential localization of effector memory cells in nonlymphoid tissue,” Science, vol. 291, no. 5512, pp. 2413–2417, 2001.

C. R. Mackay, W. L. Marston, L. Dudler, O. Spertini, T. F. Tedder, and W. R. Hein, “Tissue-specific migration pathways by phenotypically distinct subpopulations of memory T cells,” European Journal of Immunology, vol. 22, no. 4, pp. 887–895, 1992.

J. N. Agrewala, D. M. Brown, N. M. Lepak, D. Duso, G. Huston, and S. L. Swain, “Unique ability of activated CD4+ T cells but not rested effectors to migrate to non-lymphoid sites in the absence of inflammation,” The Journal of Biological Chemistry, vol. 282, no. 9, pp. 6106–6115, 2007.

R. A. Seder, P. A. Darrah, and M. Roederer, “T-cell quality in memory and protection: implications for vaccine design,” Nature Reviews Immunology, vol. 8, no. 4, pp. 247–258, 2008.

T. M. Strutt, K. K. McKinstry, Y. Kuang, L. M. Bradley, and S. L. Swain, “Memory CD4⁺ T-cell-mediated protection depends on secondary effectors that are distinct from and superior to primary effectors,” Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 38, pp. E2551–E2560, 2012.

T. M. Strutt, K. Dhume, C. M. Finn et al., “IL-15 supports the generation of protective lung-resident memory CD4 T cells,” Mucosal Immunology, vol. 11, no. 3, pp. 668–680, 2018.

G. Lauvau, M. Boutet, T. M. Williams, S. S. Chin, and L. Chorro, “Memory CD8⁺ T cells: innate-like sensors and orchestrators of protection,” Trends in Immunology, vol. 37, no. 6, pp. 375–385, 2016.

D. L. Farber, N. A. Yudanin, and N. P. Restifo, “Human memory T cells: generation, compartmentalization and homeostasis,” Nature Reviews Immunology, vol. 14, no. 1, pp. 24–35, 2014.

J. M. Schenkel and D. Masopust, “Tissue-resident memory T cells,” Immunity, vol. 41, no. 6, pp. 886–897, 2014.

S. L. Swain, K. K. McKinstry, and T. M. Strutt, “Expanding roles for CD4⁺ T cells in immunity to viruses,” Nature Reviews Immunology, vol. 12, no. 2, pp. 136–148, 2012.

M. Croft, L. M. Bradley, and S. L. Swain, “Naive versus memory CD4 T cell response to antigen. Memory cells are less dependent on accessory cell costimulation and can respond to many antigen-presenting cell types including resting B cells,” Journal of Immunology, vol. 152, no. 6, pp. 2675–2685, 1994.

M. K. L. MacLeod, A. David, A. S. McKee, F. Crawford, J. W. Kappler, and P. Marrack, “Memory CD4 T cells that express CXCR5 provide accelerated help to B cells,” Journal of Immunology, vol. 186, no. 5, pp. 2889–2896, 2011.

C. S. Ma, E. K. Deenick, M. Batten, and S. G. Tangye, “The origins, function, and regulation of T follicular helper cells,” The Journal of Experimental Medicine, vol. 209, no. 7, pp. 1241–1253, 2012.

B. J. Laidlaw, J. E. Craft, and S. M. Kaech, “The multifaceted role of CD4⁺ T cells in CD8⁺ T cell memory,” Nature Reviews Immunology, vol. 16, no. 2, pp. 102–111, 2016.

J. M. Schenkel, K. A. Fraser, L. K. Beura, K. E. Pauken, V. Vezys, and D. Masopust, “Resident memory CD8 T cells trigger protective innate and adaptive immune responses,” Science, vol. 346, no. 6205, pp. 98–101, 2014.

T. J. Chapman, K. Lambert, and D. J. Topham, “Rapid reactivation of extralymphoid CD4 T cells during secondary infection,” PLoS One, vol. 6, no. 5, article e20493, 2011.

T. M. Strutt, K. K. McKinstry, J. P. Dibble et al., “Memory CD4⁺ T cells induce innate responses independently of pathogen,” Nature Medicine, vol. 16, no. 5, pp. 558–564, 2010.

S. Ariotti, M. A. Hogenbirk, F. E. Dijkgraaf et al., “Skin-resident memory CD8⁺ T cells trigger a state of tissue-wide pathogen alert,” Science, vol. 346, no. 6205, pp. 101–105, 2014.

H. Hamada, E. Bassity, A. Flies et al., “Multiple redundant effector mechanisms of CD8⁺ T cells protect against influenza infection,” Journal of Immunology, vol. 190, no. 1, pp. 296–306, 2013.

B. Moltedo, C. B. Lopez, M. Pazos, M. I. Becker, T. Hermesh, and T. M. Moran, “Cutting edge: stealth influenza virus replication precedes the initiation of adaptive immunity,” Journal of Immunology, vol. 183, no. 6, pp. 3569–3573, 2009.

T. M. Strutt, K. K. McKinstry, Y. Kuang et al., “Direct IL-6 signals maximize protective secondary CD4 T cell responses against influenza,” Journal of Immunology, vol. 197, no. 8, pp. 3260–3270, 2016.

J. M. Reynolds, B. P. Pappu, J. Peng et al., “Toll-like receptor 2 signaling in CD4⁺ T lymphocytes promotes T helper 17 responses and regulates the pathogenesis of autoimmune disease,” Immunity, vol. 32, no. 5, pp. 692–702, 2010.

G. Caron, D. Duluc, I. Fremaux et al., “Direct stimulation of human T cells via TLR5 and TLR7/8: flagellin and R-848 up-regulate proliferation and IFN-γ production by memory CD4⁺ T cells,” Journal of Immunology, vol. 175, no. 3, pp. 1551–1557, 2005.

M. P. Ndejembi, J. R. Teijaro, D. S. Patke et al., “Control of memory CD4 T cell recall by the CD28/B7 costimulatory pathway,” Journal of Immunology, vol. 177, no. 11, pp. 7698–7706, 2006.

M. Q. Zhao, M. H. Stoler, A. N. Liu et al., “Alveolar epithelial cell chemokine expression triggered by antigen-specific cytolytic CD8⁺ T cell recognition,” The Journal of Clinical Investigation, vol. 106, no. 6, pp. R49–R58, 2000.

J. M. Schenkel, K. A. Fraser, V. Vezys, and D. Masopust, “Sensing and alarm function of resident memory CD8⁺ T cells,” Nature Immunology, vol. 14, no. 5, pp. 509–513, 2013.

S. M’Homa Soudja, C. Chandrabos, E. Yakob, M. Veenstra, D. Palliser, and G. Lauvau, “Memory-T-cell-derived interferon-γ instructs potent innate cell activation for protective immunity,” Immunity, vol. 40, no. 6, pp. 974–988, 2014.

S. R. McMaster, J. J. Wilson, H. Wang, and J. E. Kohlmeier, “Airway-resident memory CD8 T cells provide antigen-specific protection against respiratory virus challenge through rapid IFN-γ production,” Journal of Immunology, vol. 195, no. 1, pp. 203–209, 2015.

L. Min, S. A. B. Mohammad Isa, W. Shuai et al., “Cutting edge: granulocyte-macrophage colony-stimulating factor is the major CD8+ T cell-derived licensing factor for dendritic cell activation,” Journal of Immunology, vol. 184, no. 9, pp. 4625–4629, 2010.

P. A. Duttagupta, A. C. Boesteanu, and P. D. Katsikis, “Costimulation signals for memory CD8⁺ T cells during viral infections,” Critical Reviews in Immunology, vol. 29, no. 6, pp. 469–486, 2009.

J. R. Teijaro, D. Verhoeven, C. A. Page, D. Turner, and D. L. Farber, “Memory CD4 T cells direct protective responses to influenza virus in the lungs through helper-independent mechanisms,” Journal of Virology, vol. 84, no. 18, pp. 9217–9226, 2010.

K. K. McKinstry, T. M. Strutt, Y. Kuang et al., “Memory CD4⁺ T cells protect against influenza through multiple synergizing mechanisms,” The Journal of Clinical Investigation, vol. 122, no. 8, pp. 2847–2856, 2012.

M. H. Spitzer and G. P. Nolan, “Mass cytometry: single cells, many features,” Cell, vol. 165, no. 4, pp. 780–791, 2016.

M. G. Netea, L. A. B. Joosten, E. Latz et al., “Trained immunity: a program of innate immune memory in health and disease,” Science, vol. 352, no. 6284, article aaf1098, 2016.

J. C. Sun, J. N. Beilke, and L. L. Lanier, “Adaptive immune features of natural killer cells,” Nature, vol. 457, no. 7229, pp. 557–561, 2009.

S. Paust, H. S. Gill, B. Z. Wang et al., “Critical role for the chemokine receptor CXCR6 in NK cell-mediated antigen-specific memory of haptens and viruses,” Nature Immunology, vol. 11, no. 12, pp. 1127–1135, 2010.

T. E. O’Sullivan, J. C. Sun, and L. L. Lanier, “Natural killer cell memory,” Immunity, vol. 43, no. 4, pp. 634–645, 2015.

J. Goulding, R. Snelgrove, J. Saldana et al., “Respiratory infections: do we ever recover?” Proceedings of the American Thoracic Society, vol. 4, no. 8, pp. 618–625, 2007.

R. J. Snelgrove, A. Godlee, and T. Hussell, “Airway immune homeostasis and implications for influenza-induced inflammation,” Trends in Immunology, vol. 32, no. 7, pp. 328–334, 2011.

M. G. Netea, J. Quintin, and J. W. M. van der Meer, “Trained immunity: a memory for innate host defense,” Cell Host & Microbe, vol. 9, no. 5, pp. 355–361, 2011.

H. S. Goodridge, S. S. Ahmed, N. Curtis et al., “Harnessing the beneficial heterologous effects of vaccination,” Nature Reviews Immunology, vol. 16, no. 6, pp. 392–400, 2016.

J. W. Van’t Wout, R. Poell, and R. Van Furth, “The role of BCG/PPD-activated macrophages in resistance against systemic candidiasis in mice,” Scandinavian Journal of Immunology, vol. 36, no. 5, pp. 713–720, 1992.

J. Kleinnijenhuis, J. Quintin, F. Preijers et al., “Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes,” Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 43, pp. 17537–17542, 2012.

M. L. Garly, C. L. Martins, C. Bale et al., “BCG scar and positive tuberculin reaction associated with reduced child mortality in West Africa. A non-specific beneficial effect of BCG?” Vaccine, vol. 21, no. 21-22, pp. 2782–2790, 2003.

G. Walzl, I. R. Humphreys, B. G. Marshall et al., “Prior exposure to live Mycobacterium bovis BCG decreases Cryptococcus neoformans-induced lung eosinophilia in a gamma interferon-dependent manner,” Infection and Immunity, vol. 71, no. 6, pp. 3384–3391, 2003.

E. S. Barton, D. W. White, J. S. Cathelyn et al., “Herpesvirus latency confers symbiotic protection from bacterial infection,” Nature, vol. 447, no. 7142, pp. 326–329, 2007.

A. E. Williams, L. Edwards, I. R. Humphreys et al., “Innate imprinting by the modified heat-labile toxin of Escherichia coli (LTK63) provides generic protection against lung infectious disease,” Journal of Immunology, vol. 173, no. 12, pp. 7435–7443, 2004.

E. Tritto, A. Muzzi, I. Pesce et al., “The acquired immune response to the mucosal adjuvant LTK63 imprints the mouse lung with a protective signature,” Journal of Immunology, vol. 179, no. 8, pp. 5346–5357, 2007.

J. Quintin, S. Saeed, J. H. A. Martens et al., “Candida albicans infection affords protection against reinfection via functional reprogramming of monocytes,” Cell Host & Microbe, vol. 12, no. 2, pp. 223–232, 2012.

D. M. Klinman, J. Conover, and C. Coban, “Repeated administration of synthetic oligodeoxynucleotides expressing CpG motifs provides long-term protection against bacterial infection,” Infection and Immunity, vol. 67, no. 11, pp. 5658–5663, 1999.

M. Beyer, H. Bartz, K. Horner, S. Doths, C. Koerner-Rettberg, and J. Schwarze, “Sustained increases in numbers of pulmonary dendritic cells after respiratory syncytial virus infection,” The Journal of Allergy and Clinical Immunology, vol. 113, no. 1, pp. 127–133, 2004.

F. Bistoni, A. Vecchiarelli, E. Cenci, P. Puccetti, P. Marconi, and A. Cassone, “Evidence for macrophage-mediated protection against lethal Candida albicans infection,” Infection and Immunity, vol. 51, no. 2, pp. 668–674, 1986.

S.-C. Cheng, J. Quintin, R. A. Cramer et al., “mTOR- and HIF-1α–mediated aerobic glycolysis as metabolic basis for trained immunity,” Science, vol. 345, no. 6204, article 1250684, 2014.

S. Saeed, J. Quintin, H. H. D. Kerstens et al., “Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity,” Science, vol. 345, no. 6204, article 1251086, 2014.

R. L. Brown, R. P. Sequeira, and T. B. Clarke, “The microbiota protects against respiratory infection via GM-CSF signaling,” Nature Communications, vol. 8, no. 1, p. 1512, 2017.

S. Bekkering, B. A. Blok, L. A. B. Joosten, N. P. Riksen, R. van Crevel, and M. G. Netea, “In vitro experimental model of trained innate immunity in human primary monocytes,” Clinical and Vaccine Immunology, vol. 23, no. 12, pp. 926–933, 2016.

H. Weavers, I. R. Evans, P. Martin, and W. Wood, “Corpse engulfment generates a molecular memory that primes the macrophage inflammatory response,” Cell, vol. 165, no. 7, pp. 1658–1671, 2016.

N. A-Gonzalez, J. A. Quintana, S. García-Silva et al., “Phagocytosis imprints heterogeneity in tissue-resident macrophages,” The Journal of Experimental Medicine, vol. 214, no. 5, pp. 1281–1296, 2017.

A. Didierlaurent, J. Goulding, S. Patel et al., “Sustained desensitization to bacterial Toll-like receptor ligands after resolution of respiratory influenza infection,” The Journal of Experimental Medicine, vol. 205, no. 2, pp. 323–329, 2008.

E. L. Mills, “Viral infections predisposing to bacterial infections,” Annual Review of Medicine, vol. 35, no. 1, pp. 469–479, 1984.

D. M. Morens, J. K. Taubenberger, and A. S. Fauci, “Predominant role of bacterial pneumonia as a cause of death in pandemic influenza: implications for pandemic influenza preparedness,” The Journal of Infectious Diseases, vol. 198, no. 7, pp. 962–970, 2008.

K. Sun and D. W. Metzger, “Inhibition of pulmonary antibacterial defense by interferon-γ during recovery from influenza infection,” Nature Medicine, vol. 14, no. 5, pp. 558–564, 2008.

V. A. Fadok, D. L. Bratton, A. Konowal, P. W. Freed, J. Y. Westcott, and P. M. Henson, “Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF,” The Journal of Clinical Investigation, vol. 101, no. 4, pp. 890–898, 1998.

R. E. Voll, M. Herrmann, E. A. Roth, C. Stach, J. R. Kalden, and I. Girkontaite, “Immunosuppressive effects of apoptotic cells,” Nature, vol. 390, no. 6658, pp. 350-351, 1997.

K. M. Robinson, S. M. Choi, K. J. McHugh et al., “Influenza A exacerbates Staphylococcus aureus pneumonia by attenuating IL-1β production in mice,” Journal of Immunology, vol. 191, no. 10, pp. 5153–5159, 2013.

K. M. Robinson, B. Lee, E. V. Scheller et al., “The role of IL-27 in susceptibility to post-influenza Staphylococcus aureus pneumonia,” Respiratory Research, vol. 16, no. 1, p. 10, 2015.

K. L. Hartshorn, L. S. Liou, M. R. White, M. M. Kazhdan, J. L. Tauber, and A. I. Tauber, “Neutrophil deactivation by influenza a virus. Role of hemagglutinin binding to specific sialic acid-bearing cellular proteins,” Journal of Immunology, vol. 154, no. 8, pp. 3952–3960, 1995.

J. S. Abramson and E. L. Mills, “Depression of neutrophil function induced by viruses and its role in secondary microbial infections,” Reviews of Infectious Diseases, vol. 10, no. 2, pp. 326–341, 1988.

L. A. McNamee and A. G. Harmsen, “Both influenza-induced neutrophil dysfunction and neutrophil-independent mechanisms contribute to increased susceptibility to a secondary Streptococcus pneumoniae infection,” Infection and Immunity, vol. 74, no. 12, pp. 6707–6721, 2006.

K. Sun, J. Ye, D. R. Perez, and D. W. Metzger, “Seasonal FluMist vaccination induces cross-reactive T cell immunity against H1N1 (2009) influenza and secondary bacterial infections,” Journal of Immunology, vol. 186, no. 2, pp. 987–993, 2011.

R. M. Welsh, J. W. Che, M. A. Brehm, and L. K. Selin, “Heterologous immunity between viruses,” Immunological Reviews, vol. 235, no. 1, pp. 244–266, 2010.

H. D. Chen, A. E. Fraire, I. Joris, R. M. Welsh, and L. K. Selin, “Specific history of heterologous virus infections determines anti-viral immunity and immunopathology in the lung,” The American Journal of Pathology, vol. 163, no. 4, pp. 1341–1355, 2003.

A. Gil, L. L. Kenney, R. Mishra, L. B. Watkin, N. Aslan, and L. K. Selin, “Vaccination and heterologous immunity: educating the immune system,” Transactions of the Royal Society of Tropical Medicine and Hygiene, vol. 109, no. 1, pp. 62–69, 2015.