REVIEW
Immunodominance: A pivotal principle in host response to viral infections

https://doi.org/10.1016/j.clim.2012.01.015Get rights and content

Abstract

We encounter pathogens on a daily basis and our immune system has evolved to mount an immune response following an infection. An interesting phenomenon that has evolved in response to clearing bacterial and viral infections is called immunodominance. Immunodominance refers to the phenomenon that, despite co-expression of multiple major histocompatibility complex class I alleles by host cells and the potential generation of hundreds of distinct antigenic peptides for recognition following an infection, a large portion of the anti-viral cytotoxic T lymphocyte population targets only some peptide/MHC class I complexes. Here we review the main factors contributing to immunodominance in relation to influenza A and HIV infection. Of special interest are the factors contributing to immunodominance in humans and rodents following influenza A infection. By critically reviewing these findings, we hope to improve understanding of the challenges facing the discovery of new factors enabling better anti-viral vaccine strategies in the future.

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.

References (149)

  • H.P. Raue et al.

    CD8 + T cell immunodominance shifts during the early stages of acute LCMV infection independently from functional avidity maturation

    Virology

    (2009)
  • S. Siddiqui et al.

    Altered immunodominance hierarchies of CD8 + T cells in the spleen after infection at different sites is contingent on high virus inoculum

    Microbes Infect.

    (2010)
  • A. Wieland et al.

    Silencing an immunodominant epitope of hepatitis B surface antigen reveals an alternative repertoire of CD8 T cell epitopes of this viral antigen

    Vaccine

    (2009)
  • N.J. Cox et al.

    Influenza

    Lancet

    (1999)
  • N. Hu et al.

    Highly conserved pattern of recognition of influenza A wild-type and variant CD8 + CTL epitopes in HLA-A2 + humans and transgenic HLA-A2+/H2 class I-deficient mice

    Vaccine

    (2005)
  • R. Meijers et al.

    Crystal structures of murine MHC Class I H-2 D(b) and K(b) molecules in complex with CTL epitopes from influenza A virus: implications for TCR repertoire selection and immunodominance

    J. Mol. Biol.

    (2005)
  • P.M. Kloetzel et al.

    Proteasome and peptidase function in MHC-class-I-mediated antigen presentation

    Curr. Opin. Immunol.

    (2004)
  • A.F. Kisselev et al.

    The sizes of peptides generated from protein by mammalian 26 and 20 S proteasomes. Implications for understanding the degradative mechanism and antigen presentation

    J. Biol. Chem.

    (1999)
  • A.L. Goldberg et al.

    The importance of the proteasome and subsequent proteolytic steps in the generation of antigenic peptides

    Mol. Immunol.

    (2002)
  • T. Saric et al.

    Major histocompatibility complex class I-presented antigenic peptides are degraded in cytosolic extracts primarily by thimet oligopeptidase

    J. Biol. Chem.

    (2001)
  • G. Velarde et al.

    Three-dimensional structure of transporter associated with antigen processing (TAP) obtained by single particle image analysis

    J. Biol. Chem.

    (2001)
  • N. Blanchard et al.

    Coping with loss of perfection in the MHC class I peptide repertoire

    Curr. Opin. Immunol.

    (2008)
  • Y. Kawashima et al.

    Different immunodominance of HIV-1-specific CTL epitopes among three subtypes of HLA-A*26 associated with slow progression to AIDS

    Biochem. Biophys. Res. Commun.

    (2008)
  • A.L. Ackerman et al.

    Early phagosomes in dendritic cells form a cellular compartment sufficient for cross presentation of exogenous antigens

    Proc. Natl. Acad. Sci. U. S. A.

    (2003)
  • A.L. Ackerman et al.

    Cellular mechanisms governing cross-presentation of exogenous antigens

    Nat. Immunol.

    (2004)
  • R.M. Zinkernagel et al.

    Restriction of in vitro T cell-mediated cytotoxicity in lymphocytic choriomeningitis within a syngeneic or semiallogeneic system

    Nature

    (1974)
  • M.F. Mescher

    Molecular interactions in the activation of effector and precursor cytotoxic T lymphocytes

    Immunol. Rev.

    (1995)
  • M. Barry et al.

    Cytotoxic T lymphocytes: all roads lead to death

    Nat. Rev. Immunol.

    (2002)
  • S.M. Kaech et al.

    Effector and memory T-cell differentiation: implications for vaccine development

    Nat. Rev. Immunol.

    (2002)
  • M.J. Bevan

    Helping the CD8(+) T-cell response

    Nat. Rev. Immunol.

    (2004)
  • R.A. van Lier et al.

    Human CD8(+) T-cell differentiation in response to viruses

    Nat. Rev. Immunol.

    (2003)
  • J.W. Yewdell et al.

    Immunodominance in major histocompatibility complex class I-restricted T lymphocyte responses

    Annu. Rev. Immunol.

    (1999)
  • E.E. Sercarz et al.

    Dominance and crypticity of T cell antigenic determinants

    Annu. Rev. Immunol.

    (1993)
  • E. Cheuk et al.

    Human MHC class I transgenic mice deficient for H2 class I expression facilitate identification and characterization of new HLA class I-restricted viral T cell epitopes

    J. Immunol.

    (2002)
  • A.M. Deckhut et al.

    Prominent usage of V beta 8.3 T cells in the H-2Db-restricted response to an influenza A virus nucleoprotein epitope

    J. Immunol.

    (1993)
  • A.D. Kelleher et al.

    Clustered mutations in HIV-1 gag are consistently required for escape from HLA-B27-restricted cytotoxic T lymphocyte responses

    J. Exp. Med.

    (2001)
  • I.E. Flesch et al.

    Altered CD8(+) T cell immunodominance after vaccinia virus infection and the naive repertoire in inbred and F(1) mice

    J. Immunol.

    (2010)
  • M.F. Kotturi et al.

    Of mice and humans: how good are HLA transgenic mice as a model of human immune responses?

    Immunome Res.

    (2009)
  • S. Remakus et al.

    Gamma interferon and perforin control the strength, but not the hierarchy, of immunodominance of an antiviral CD8+ T cell response

    J. Virol.

    (2011)
  • D.S. Boulanger et al.

    Absence of tapasin alters immunodominance against a lymphocytic choriomeningitis virus polytope

    J. Immunol.

    (2010)
  • M. Reiser et al.

    The immunodominant CD8 T cell response to the human cytomegalovirus tegument phosphoprotein pp 65495-503 epitope critically depends on CD4 T cell help in vaccinated HLA-A*0201 transgenic mice

    J. Immunol.

    (2011)
  • M.W. Munks et al.

    Viral interference with antigen presentation does not alter acute or chronic CD8 T cell immunodominance in murine cytomegalovirus infection

    J. Immunol.

    (2007)
  • P. Riedl et al.

    Elimination of immunodominant epitopes from multispecific DNA-based vaccines allows induction of CD8 T cells that have a striking antiviral potential

    J. Immunol.

    (2009)
  • J. Schmidt et al.

    Immunodominance of HLA-A2-restricted hepatitis C virus-specific CD8 + T cell responses is linked to naive-precursor frequency

    J. Virol.

    (2011)
  • J. Zlatkovic et al.

    Immunodominance and functional activities of antibody responses to inactivated West Nile virus and recombinant subunit vaccines in mice

    J. Virol.

    (2011)
  • D.H. Busch et al.

    MHC class I/peptide stability: implications for immunodominance, in vitro proliferation, and diversity of responding CTL

    J. Immunol.

    (1998)
  • L. Kjer-Nielsen et al.

    The structure of HLA-B8 complexed to an immunodominant viral determinant: peptide-induced conformational changes and a mode of MHC class I dimerization

    J. Immunol.

    (2002)
  • A. Portela et al.

    The influenza virus nucleoprotein: a multifunctional RNA-binding protein pivotal to virus replication

    J. Gen. Virol.

    (2002)
  • D.L. Woodland et al.

    Cellular immunity and memory to respiratory virus infections

    Immunol. Res.

    (2001)
  • M.J. Pinkoski et al.

    Lymphocyte apoptosis: refining the paths to perdition

    Curr. Opin. Hematol.

    (2002)
  • Cited by (85)

    • Therapeutic cancer vaccines revamping: technology advancements and pitfalls

      2021, Annals of Oncology
      Citation Excerpt :

      To do so, standardized bioinformatic tools able to identify and prioritize possible tumor-specific mutations have been developed.123 However, not all mutations result in neoepitopes that are recognized by the immune system, owing to HLA restriction/immunodominance.59,62 Therefore, HLA typing is also required to foresee potentially immunogenic epitopes.42

    • Integrative proteomics identifies thousands of distinct, multi-epitope, and high-affinity nanobodies

      2021, Cell Systems
      Citation Excerpt :

      Like IgG antibodies, Nbs also prefer a handful of specific epitopes. Such immunodominance may help to efficiently elicit the response to bind antigens tightly (Akram and Inman, 2012). Moreover, we identified a large spectrum of high-affinity Nbs (hAbs) in circulation with diverse CDR sequences that bind the same or an overlapping epitope.

    View all citing articles on Scopus

    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.

    View full text