Immunity to viruses

This article introduces a series of reviews covering Immunity to Viruses appearing in Volume 255 of Immunological Reviews. The analysis of the innate and adaptive immune response to viruses has provided fundamental insight into the functioning of the immune system. Early studies on the host response to virus infection were instrumental in establishing the concept of immunological tolerance 1. Similarly, the realization that T lymphocytes are ‘restricted’ in their recognition of antigens by gene products encoded within the major histocompatibility complex (MHC) locus came from the analysis of T-lymphocyte recognition of virus-infected cells 2. Likewise, important initial insights into antigen processing and presentation came from the analysis of viruses and virus-infected cells 3, 4. Until recently, it was convenient to view immunity to infectious agents like viruses as a separate branch of immunology distinct from immunity to tumors, self-molecules (antigens), or allergens. As demonstrated in many of the articles in this volume of Immunological Reviews, the mechanisms underlying the induction and regulation of the innate and adaptive immune response to viruses represent the same processes controlling immunity to tumor antigens, allergens, and self-constituents. Thus, the results summarized in these review articles and the implications of these findings are applicable not only to those of us who study immunity to viruses but also to the immunology community at large. In selecting the topics for review in this volume of Immunological Reviews, we were first and foremost limited by space. Consequently, many important contributors to the field of viral immunology (indeed several topics) are not represented in this volume. Our selection of topics and authors was biased toward emerging areas, such as the application of systems biology approaches to viral pathogenesis and immunity, the contribution of inflammatory and stress responses to the induction of innate and adaptive immune responses, and the impact of the microbiome on immunity to virus infection. We also considered it relevant to include reviews focused on well-defined areas where recent findings have resulted in potential paradigm shifts in our understanding of topics such as B-lymphocyte or T-lymphocyte responses to virus infection. This volume of Immunological Reviews is also somewhat weighted toward analyses of the immune response to respiratory viruses. With the recent episodic infections with the severe acute respiratory syndrome-like coronavirus and the outbreak of human infections with the avian influenza A H7N9 virus, respiratory viruses such as these organisms are recognized as major human pathogens with the potential for pandemic spread. Therefore, this class of viruses is a focus of immunological research. The reviews in this volume can be grouped according to the following scheme: (i) molecules and cells regulating the induction of the innate and adaptive response; (ii) expression of immune effector activity; (iii) regulation of the antiviral immune response; and (iv) systems analysis of the host response to infection and vaccination (Fig. 1). The initiation of the immune response to an invading microorganism like a virus requires that the host senses the organism and its constituents [e.g. uncapped viral RNA 5] and/or cellular stress and consequent metabolic changes and cellular damage resulting from infection. This initial response to infection is carried out primarily by germline-encoded pattern recognition receptors (PRRs) 5, 6. Five types of PRRs have been identified. These include C-type lectin receptors and Toll-like receptors (TLRs) localized to the cell surface or within endosomes and intracellular retinoic acid inducible gene-I-like receptors (RLRs), nucleotide oligomerization, and binding domain-like receptors (NLRs), and the Pyrin-HIN domain (PYHIN) receptors 5, 7, 8. Each of these receptor types has multiple members, and individual members of a receptor type variously recognize pathogen-associated products or damage-associated molecular patterns, such as reactive oxygen species, adenosine triphosphate, or apoptotic/necrotic cells 9. The role of sensors such as TLRs and RLRs in virus infection is well established 5, 8. By contrast, the extent of the contribution of NLRs in the recognition of virus and virus-infected cells has only been appreciated more recently 10. NLRs are a large receptor family including at least 20 members. NLRs play a dominant role in inflammasome activation resulting in the Caspase-1-dependent maturation and release from cells of the pro-inflammatory mediators interleukin-1 (IL-1) and IL-18. However, not all NLRs are pro-inflammatory. Engagement of certain members of this receptor family can downregulate pro-inflammatory signals generated by other PRR types 11. In addition, several NLRs have been reported to regulate antigen presentation events associated with the MHC class I and II presentation pathways 12, 13. In their review of the role of NLRs in antiviral immunity, Lupfer and Kanneganti 14 examine the role of specific NLRs in inflammasome activation and regulation during virus infection and the contribution of other NLRs to the regulation of inflammation and viral antigen presentation during virus infection. One of the critical consequences of the engagement of certain PRR types, e.g. TLRs and RLRs by virus infection, is the induction of the interferon (IFN) response. Type I IFNs were initially identified and named based on their antiviral properties. However, in addition to upregulating genes that inhibit virus replication, this class of cytokines has been appreciated to play an important role in orchestrating the adaptive immune response to virus infection. Recently, a new family of antiviral cytokines, the type III IFN family, has been identified. The type III IFNs (also known as IFN λ 1, 2, 3 or IL-29, IL-28A, IL-28B, respectively) appeared to activate the same antiviral pathways and transcriptional factors, e.g. IFN-stimulated gene factor 3, as the type I IFNs. However, the type III IFNs have little structural homology with their type I counterparts and engage a distinct heterodimeric receptor, which includes the IL-10R2 chain 15. In their article, Durbin and coworkers 16 summarize the current understanding of antiviral signaling by type I and type III IFNs, with particular emphasis on the induction of these cytokines and the expression of antiviral activity of these two cytokine families at mucosal surfaces, notably the respiratory tract and gut following infection with influenza A virus (IAV), respiratory syncytial virus, or rotavirus. They also summarize our current understanding of the immunomodulatory effects of these cytokines on the induction of the adaptive immune response through their effect on specific cell types, for example natural killer (NK) cells and dendritic cells (DCs) 17, and the distinct signal transduction events associated with immune modulation by IFN. Another important consequence of PRR engagement in response to microbial infection is the induction of the autophagy response. Autophagy is a catabolic recycling pathway induced by stress, e.g. the endoplasmic reticulum stress response 18. Microbial infection promotes autophagy by a variety of mechanisms 19. In their review on the impact of autophagy on CD8+ T-cell-mediated antiviral immunity, Perot and colleagues 20 review the complex interplay between viruses and three pathways of response to virus infection, that is autophagy, the innate immune response, and the adaptive immune response. In this article, the authors describe the subcellular constituents making up the autophagy response and strategies that viruses employ to either enhance or inhibit autophagy and the consequences of alterations in autophagy on innate and adaptive immune response induction. Of particular note is the recent evidence on the contribution of autophagy to viral antigen processing and presentation to CD8+ T cells. They further extend this analysis to evaluate the impact of autophagy on T-cell differentiation in the thymus in the process of lymphocyte activation in the periphery. DCs are cellular sentinels that link the innate and adaptive immune systems. As a cell type, they are well endowed with a range of PRR sensors for both pathogen-associated ligands and damage-associated ligands generated during virus infection. This sentinel role is particularly crucial at body surfaces such as the skin, gastrointestinal tract, and lungs, which are the major sites of pathogenic microorganism entry into the body. Although distinct from macrophages, DCs are not a uniform population but exist as distinct subsets with different properties/functions, in different activation states dependent upon the site of DC localization, i.e. in secondary lymphoid tissue, deep in body tissues, or at mucosal surfaces. Neyt and Lambrecht 21 review the lung DCs, their diversity, function in the steady state and following lung inflammation, as well as activation in response to respiratory virus infection. This report examines the consequences of direct activation of DCs by virus infection as well as indirect or trans activation of DCs by products released by airway epithelial cells, themselves responding to engagement of their PRRs by virus or cellular stress. For example, IL-1 produced by respiratory epithelial cells following PRR engagement acts in an autocrine fashion to release DC-attracting chemokines as well as granulocyte-macrophage colony-stimulating factor to support DC recruitment and viability and factors involved in epithelial regeneration (IL-33). DC migration from the lungs to the draining lymph nodes is an essential step in the initiation of the antiviral T-cell response. Type I IFNs are the most potent inducers of DC maturation resulting in DC migration 22. This report also reviews current findings on the role of individual DC subsets in orchestrating different aspects of the adaptive immune response, including the dominant role of the CD8a/CD 103+ DC family in cross-presenting viral pathogen to naive CD8+ T cells and the role of C-type lectins (most notably DNGR-1) in capturing viral antigen delivered by dying epithelial cells 23. This report points to the ‘division of labor’ among DC subsets in the induction of antiviral effector responses and in the control of local inflammation at the site of infection, i.e. the respiratory tract. NK cells serve as major innate immune effector cells functioning in the control of virus infection 24. They simultaneously display germline-encoded activating and inhibitory receptors in various combinations on a given cell. The inhibitory receptors are sensitive to the level of expression of MHC class I molecules on cell surfaces, so-called ‘missing self’ 25. NK cells also display PRRs, which respond to pathogen-derived and/or damage-induced ligands. NK cells have been implicated in control of infection with the number of viruses both in human and in experimental models. One human virus infection where NK cells have been implicated to play a role both in control of virus replication as well as in the development and control of tissue damage is chronic infection with hepatitis C virus (HCV). Approximately 150–200 million people worldwide are estimated to have chronic HCV infection. HCV persists in up to 80% of infected individuals with only a minority of individuals clearing infection without therapeutic intervention. The ability of this virus to persist in such a large fraction of infected individuals suggests that it is capable of dysregulating the host innate and adaptive immune response to allow its persistence in the liver. Although modified IFN-based regimens have been the standard of treatment for HCV for more than a decade, success rates vary substantially depending on the genotype of HCV infecting the patient. Understanding the mechanisms that regulate immunity against this virus in the liver and in particular the contribution of NK cells to resistance and recovery from infection is essential the development of improved therapies and ultimate cures. In their article, Golden-Mason and Rosen 26 review basic aspects of the biology of NK cells including the process of NK cell activation and the NK cell molecules that control the activation state of NK cells. They then go on to focus on the role and properties of NK cells during the acute and chronic stages of HCV infection, the impact of treatment on NK cell responses with emphasis on the properties of NK cells specifically localized to the liver ,and the effect of HCV infection on the properties and function of liver NK cells. They conclude with an analysis of NK cells as regulators of liver fibrosis, crosstalk between NK cells and DCs, and speculate on the potential role of NK cell memory 27 following infection and the prospects for the development of vaccines targeted to NK cells. In her review of B-cell responses to virus infection, Baumgarth 28 takes us to the interface between the innate and the adaptive immune response to virus. Using IAV as a model system, she explores the development and role of polyreactive natural antibody B-cell responses and the role and function of germinal center B-cell responses in infection. Polyreactive natural antibodies are largely of the immunoglobulin M (IgM) class and are generated independent of antigen challenge 29 by a distinct class of B lymphocytes, B-1 (CD5+ B-1a, and CD5-B-1b) B cells. The immunoglobulin receptor on B-1 cells is diverse but does not normally undergo Ig class switch. B-1 cells and their natural antibody products were initially believed to be self-reactive and potentially capable of producing autoimmunity. However, it is becoming increasingly clear that they can bind pathogen-associated antigens. B-1 lymphocytes qualify as innate immune cells much like NKT cells, which also rearrange their receptor genes, but unlike NKT cells exhibit considerable diversity in V gene usage. The polyreactive nature of these antibodies is due to the pentameric structure of the IgM immunoglobulin. The development, function, and regulation of the B-1 lymphocytes and their natural antibody products are discussed in the context of their role in IAV infection 28. The impact of B-1 lymphocytes on influenza infection discussed in relation to the response of conventional extrafollicular and germinal center B-2 B lymphocytes. The article concludes with evidence suggesting that repertoire diversity and broadly cross-reactive polyreactive B-cell responses, as exhibited by B-1 and extrafollicular B-2 responses, may be more important than B-cell affinity maturation (in the germinal center) for effective B-cell immunity to pathogens like IAV, which can undergo rapid antigenic variation. The sine qua non of the adaptive immune response is the apparent exquisite specificity of individual B and T lymphocytes. However, as the aforementioned description of B-1 B cells and polyreactive natural antibodies suggest, this apparent high degree of specificity was not always observed. In the case of T lymphocytes, there were multiple early examples of T-cell cross-reactivity for apparently unrelated antigens 30. Perhaps this was best exemplified from the early studies of Welsh and coworkers 31, 32 demonstrating cross-reactive recognition of heterologous viruses by memory CD8+ T cells. Su and Davis 33 review the topic of T-cell receptor (TCR) cross-reactivity in the development of CD4+ memory T-cell responses in both the mouse and human. This detailed review covers topics ranging from the pre-immune T-cell repertoire and the structural basis of T-cell cross-reactivity for seemingly unrelated viruses to the functional consequences of TCR cross-reactivity and the contribution of the microbiome to regulating the T-cell repertoire and TCR cross-reactivity on the development on human disease and responsiveness to vaccination. Moseman and McGavern 34 with the of the consequences of TCR engagement of with specific emphasis on the and in of immunological They review the evidence for and against the for the of a immunological to signaling events and to effector activity in CD4+ and CD8+ effector T cells. They employ to on the of T-lymphocyte with on infected cells in the model of infection in the system. most recent evidence suggests that effective between T cells and virus-infected cell resulting in virus or in can be either immunological or depending on the cell type and the extent of that or activity following engagement of their ligands play a role in all aspects the adaptive immune response to virus infection. Engagement of receptors is for the activation naive antiviral T cells. and receptors and their ligands can the differentiation of T cells into effector or memory cells at critical during the of the of the antiviral T-cell response, controlling the of the T-cell response at the site of infection and the potential for tissue and review the role of tumor factor receptor family members in antiviral immunity, members that primarily serve a role in antiviral CD8+ T cells but can in the antiviral T-cell response, i.e. exhibit activity the receptor is They also the potential role of ligands as and family members as for therapeutic in chronic viral The topic of CD4+ T-cell differentiation and regulation of development of specific CD4+ T-cell subsets has been a topic in Immunological Reviews. The has a in the number of effector CD4+ T-cell subsets from two to at least In their article, the of an view of the role of several of these effector CD4+ T-cell subsets and the memory T-cell in response to experimental IAV infection. They their studies on the between effector CD4+ T cells and conventional effector CD4+ T cells in virus and recovery from IAV infection. They review the evidence for of function of various effector CD4+ T-cell subsets and the of of responding CD4+ T cells and the expression of effector They also the evidence for regulation of effector in lymphoid and by CD4+ T cells can be into subsets based on their functional properties and effector memory T cells can be into subsets based on their and properties. For more than a decade, memory T cells were into memory and T memory cells. cells primarily through tissues, through and to secondary lymphoid recently, analyses have identified a memory T-cell the T memory cells cells primarily to and are in The and at these sites expression of specific and and based on the of these in the or state to effector T cells or the several subsets of memory T cells. They review the mechanisms regulating the migration of memory T cells in the steady state and in response to inflammation in particular virus They describe the factors that control the of cells and the properties that from the and cell they the potential role of cells in vaccination against pathogens that the body through of the potential to as a of recognition of an invading the innate and adaptive immune systems have multiple mechanisms to control the and of the immune response. One of the most important cell types involved in the control of the responses is the T cell. and focus on the CD4+ T cells the factor 3 and the contribution of this T-cell to antiviral They describe the mechanisms by which viruses responses from natural as well as inducible which are from naive CD4+ T cells. They the where antiviral T-cell responses or control They in the potential role of in chronic infection with human virus and HCV and the potential therapeutic of responses to the of virus infection, particularly in the context of chronic inflammation and associated with virus infection. The has carried out studies on the link between virus infection antiviral immunity and the development of responses mechanisms by which virus infection results in local or e.g. T-cell responses induced by viral molecular as well as more mechanisms of induction of responses, such as mechanisms to immune recognition events resulting in cells are cells that were initially in the and in the of human least two of have been identified properties of either or cells. As their they are potent of immune In recent evidence has that may play a role in immune by particularly viruses that can infection. In their the mechanisms involved in the and and of during virus infection and the critical of including T cells, NK cells, and cells. They go on to the of viral infections in which the activity of has been reported and then as for therapeutic in the treatment of chronic virus In regulation of the immune response, of the most areas to have recently is the evidence the and of the immune response to the host i.e. the this topic has been the of recent reviews in Immunological Reviews, and colleagues focus their article on the impact of on the host response to virus infection, as exemplified by the impact of all on IAV pathogenesis and the host adaptive response to the virus We are in the early in our understanding of the role of in controlling innate and adaptive immune responses to but as in this volume are emerging to both and potentially effects of on the antiviral immune response and of virus infection. The development of high as well as in and have up new and for the analysis of the host response to virus infection as well as reviews the and in the development of effective viral on development and vaccination strategies in the context of antibodies and/or CD8+ T-cell responses and the and of vaccination to on to describe the impact of new notably high and the application of structural biology approaches to antigen on concludes with a of the prospects for effective development against emerging viruses and viruses with the potential for producing chronic infection. 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