REVIEWImmunodominance: A pivotal principle in host response to viral infections☆
Highlights
► Immunodominance (ImDc) plays an important role following viral infections. ► HIV-1 and influenza infections lead to immunodominant responses in animals. ► Immunodominant peptides are preferentially recognized by host’s immune system. ► Antigen processing/presentation steps contribute to ImDc following an infection. ► Viral mutation, CD8 T cell precursor number and memory T cells contribute to ImDc.
Introduction
On a daily basis we come into contact with wide range of pathogens. These potentially pathogenic encounters may be airborne or by direct contact. In some cases proximity to particular pathogens determines whether infection will ensue. Examples of airborne diseases include anthrax and flu. In the case of acquired immune deficiency syndrome (AIDS), caused by human immunodeficiency virus (HIV), transmission is predominantly by way of body fluid exchange through sexual contacts. Overall, some potential pathogens are harmless and may be ‘ignored’ by our immune system, whereas other pathogenic encounters can cause a robust immune response involving both the innate and the adaptive arms of the immune system.
Innate immunity is the first line of defense against pathogens. Upon infection, key elements of innate immunity, such as macrophages and neutrophils, may successfully limit and non-specifically clear pathogens by inducing acute inflammatory responses, including IFN-γ production. This process allows the adaptive immunity to mount a more specific response 4 to 5 days post-infection. B and T lymphocytes along with dendritic cells (DC) are amongst the central elements of adaptive immunity. Following an infection, a complex multi-step sequence involving the processing of different proteins leads to generation of antigenic peptides. These peptides are then presented on the cell surface by major histocompatibility complex (MHC) class I and II molecules. MHC class I molecules mostly present peptides derived from cytosolic proteins. Viral proteins provide an important source of foreign peptides presented by MHC class I molecules. While it was assumed for some time that endogenous peptides were only presented by MHC class I and exogenous peptides by MHC class II, recent findings [1], [2], [3], [4] have shown that class I molecules are also capable of presenting exogenous peptides through cross presentation.
The crucial first step in adaptive immunity following viral infection is the activation of naive antigen-specific T cells by antigen presenting cells (APCs) in the lymphoid organs. During T cell development thymocytes undergo a complex process involving both positive and negative selection. The cells surviving these selection processes mature into naive T cells. These T cells respond to viral antigens only if they are presented peptides in the context of self-MHC molecules (i.e., pMHC) on the surface of APCs [5]. Both the MHC molecule and its bound peptide have to be recognized by specific T cell receptors (TCR) in order to initiate T cell activation [5]. Interactions of co-stimulatory molecules with their ligands also contribute to the overall T cell activation following initial pMHC–TCR interaction.
CD8+ T cell activation is initiated by the interaction of a TCR–CD3 complex with a pMHC class I complex (i.e., pMHC-I) [6]. MHC class I proteins consist of a highly polymorphic heavy chain (HC) and monomorphic β2-microglobulin (β2m). The HC is made up of three extra-cellular domains (i.e., α1, α2 and α3), a transmembrane domain (TM) and a cytoplasmic domain [5]. TCR makes contact with both α1 and α2 domains of the MHC class I molecule as well as its bound peptide, whereas CD3 helps in signal transduction initiated by this interaction [6]. Activation is further promoted by the interaction of the co-receptor molecule CD8 with the pMHC-I complex [6]. This interaction of TCR–CD3 complex with a pMHC-I complex enables the T cell and the APC to juxtapose, allowing for interaction of other molecules with their respective ligands (e.g., CD80 or CD86 with CD28 or LFA-1 with ICAM-1). Activated CD8+ cytotoxic T lymphocytes (CTLs) have the capacity to destroy infected target cells through release of membrane disintegrating proteins, such as perforins, or induction of apoptosis through the Fas/FasL pathway [7].
After pathogen elimination, the expanded antigen-specific T cell pool contracts substantially through apoptosis and only about 10% of the antigen-stimulated T cells persist as memory cells [8], [9]. Memory T cells provide enhanced protection after re-infection because of their increased precursor frequency compared with the naive repertoire, and their ability to proliferate and carry out effector functions at the site of infection. In addition, memory T cells, unlike naive T cells, do not require further priming and yet express high affinity receptors (e.g., CD25) for cytokines essential for their survival and function. How memory T cells develop from the initial pool of activated T cells is still not completely understood. Different models have been proposed on how memory cells are formed in responses to distinct viruses (e.g., influenza) [9], [10], [11]. By whatever mechanisms, memory cells may persist for extended time periods ranging from weeks to months (in mice) or to years (in humans) depending on the organism [9]. Re-infection with the same virus initiates clonal expansion of effector T cells from these memory pools and leads to an increase in the antigen-specific T cell population in the memory state [11], [12].
Another key player involved in adaptive immunity is the B lymphocyte. In short, following viral infections B cells are activated in part by cytokines, such as interleukin-2, released by activated CD4+ T cells. Activated B cells can mature to plasma cells with subsequent release of antibodies specific for antigenic cell surface proteins. This facilitates elimination of pathogens by opsonization and complement activation. While generally B cells act in concert with cytotoxic T lymphocytes for effective elimination of viral infection, CTL generating immunodominant responses appear to play a more central role than B cells or CD4+ T cells. This review will discuss only factors contributing to immunodominance in relation to CTL responses in the context of MHC class I molecules.
Section snippets
Importance of immunodominance in immune response
Following a viral infection, CD8+ CTL recognize viral antigenic peptides bound with a self-MHC class I molecule on the surface of an infected cell and are thereby activated to lyse that target cell [11], [12]. A central feature of many anti-viral T cell responses is the phenomenon of immunodominance (ImDc). This refers to the observation that, despite the co-expression of 3–6 different MHC class I molecules on APC, and the potential generation of hundreds to thousands of distinct 8 to 11-mer
Immunodominance is common following both viral and bacterial infections
Not all host-pathogen interactions are associated with ImDc, yet the prevalence of ImDc is very common. There have been examples of ImDc in response to infections caused by the vaccinia virus [23], [24], [25], [26], lymphocytic choriomeningitis virus (LCMV) [27], [28], [29], human cytomegalovirus (CMV) [30], [31], hepatitis B virus (HBV) [32], [33], hepatitis C virus (HCV) [34], West Nile virus [35], Listeria [36], and Epstein–Barr virus (EBV) [37]. Since the preponderance of studies dissecting
Factors influencing ImDc in flu and HIV-1 infections
The dominant factors contributing to ImDc are listed in Table 1 and most of these factors are shown in Fig. 1. The factors contributing to ImDc function either alone or in combination. These factors play an important role in ImDc regardless of viral type. A number of studies have shown evidence of ImDc or a shift of ImDc in flu-infected mice. Most of the anti-viral CTL responses are directed against the H2-Db/NP366-374 peptide in flu-infected wild type (WT) mice [18], [19], [45], [46], [47],
Summary
Immunodominance plays a critical role in the ability to mount a specific immune response. Studies discussed here suggest that there are a number of different factors contributing to ImDc seen with flu and HIV-1 infected individuals. Some of these factors contribute to ImDc more (e.g., prevalence of peptide-specific T cell precursors) than others following a viral infection. An analogy to immunodominant responses following viral infection is a soccer team consisting of different players. By
Conflict of interest statement
The authors declare that there are no conflicts of interest.
Acknowledgments
Mr. Ali Akram is supported by scholarships from Arthritic Centre of Excellence (ACE) and Queen Elizabeth II Graduate scholarships in Science and Technology (QEII-GSST). Dr. Robert Inman is supported by grants from Canadian Institute of Health Research (CIHR). We would like to thank Dr. N. Haroon and Ghizal Akram for their thoughtful contribution to this manuscript.
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This work was supported by scholarships received by Ali Akram [M.Sc., Ph.D. (c)] from the Arthritis Centre for Excellence (ACE) and Queen Elizabeth II Graduate scholarship in Science and Technology (QEII-GSST) from University Health Network and University of Toronto. Ali Akram is also supported by a CIHR grant received by Dr. Robert D. Inman.