Immunodominance

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Jonathan W Yewdell - One of the best experts on this subject based on the ideXlab platform.

  • Is It Possible to Develop a “Universal” Influenza Virus Vaccine? Outflanking Antibody Immunodominance on the Road to Universal Influenza Vaccination
    Cold Spring Harbor Perspectives in Biology, 2018
    Co-Authors: Davide Angeletti, Jonathan W Yewdell
    Abstract:

    Influenza remains a major human pathogen despite seasonal vaccination. At long last, there is energy and resources to develop influenza vaccines that provide more predictable and durable protection. Vaccines based on inducing antibodies to the conserved stem of the viral hemagglutinin (HA) have emerged as leading candidates for broadening population immunity and ultimately limiting antigenic drift. Here, we discuss the knowns and unknowns of HA-specific B-cell and antibody responses. In particular, we focus on how Immunodominance sculpts antibody responses and drives antigenic drift. We propose a number of strategies to overcome Immunodominance and improve the breadth and efficacy of antibody responses.

  • is it possible to develop a universal influenza virus vaccine outflanking antibody Immunodominance on the road to universal influenza vaccination
    Cold Spring Harbor Perspectives in Biology, 2018
    Co-Authors: Davide Angeletti, Jonathan W Yewdell
    Abstract:

    Influenza remains a major human pathogen despite seasonal vaccination. At long last, there is energy and resources to develop influenza vaccines that provide more predictable and durable protection. Vaccines based on inducing antibodies to the conserved stem of the viral hemagglutinin (HA) have emerged as leading candidates for broadening population immunity and ultimately limiting antigenic drift. Here, we discuss the knowns and unknowns of HA-specific B-cell and antibody responses. In particular, we focus on how Immunodominance sculpts antibody responses and drives antigenic drift. We propose a number of strategies to overcome Immunodominance and improve the breadth and efficacy of antibody responses.

  • confronting complexity real world Immunodominance in antiviral cd8 t cell responses
    Immunity, 2006
    Co-Authors: Jonathan W Yewdell
    Abstract:

    Antiviral CD8 + T cells respond to only a minute fraction of the potential peptide determinants encoded by viral genomes. Immunogenic determinants can be ordered into highly reproducible hierarchies based on the magnitude of cognate CD8 + T cell responses. Until recently, this phenomenon, termed Immunodominance, was largely defined and characterized in model systems utilizing a few strains of inbred mice infected with a handful of viruses with limited coding capacity. Here, I review work that has extended Immunodominance studies to viruses of greater complexity and to the real world of human antiviral immunity.

  • reversal in the Immunodominance hierarchy in secondary cd8 t cell responses to influenza a virus roles for cross presentation and lysis independent immunodomination
    Journal of Immunology, 2004
    Co-Authors: Weisan Chen, Jack R Bennink, Sameh Basta, Nektaria Dimopoulos, Ken C Pang, Kellyanne Masterman, Gina Kennedy, Felicita Hornung, Mark J Smyth, Jonathan W Yewdell
    Abstract:

    Immunodominance is a central feature of CD8 + T cell (T CD8 + ) responses to pathogens, transplants, and tumors. Determinants occupy a stable position in an Immunodominance hierarchy (α-, β-, etc.) defined by the frequencies of responding T CD8 + . In this paper, we study the mechanistic basis for place-swapping between α- (acid polymerase (PA) 224–233 ) and β-determinants (nuclear protein 366–374) in primary vs secondary anti-influenza A virus (IAV) responses in mice. This phenomena was recently correlated with the inability of IAV-infected nondendritic cells (DCs) to generate PA 224–233 , and it was proposed that secondary T CD8 + are principally activated by IAV-infected epithelial cells, while primary T CD8 + are activated by IAV-infected DCs. In this study, we show that the inability of non-DCs to generate PA 224–232 is relative rather than absolute, and that the preferential use of cross-priming in secondary anti-IAV responses can also account for the revised hierarchy. We further show that immunodomination of PA 224–233 -specific T CD8 + by nucleoprotein 366–374-specific T CD8 + plays a critical role in the phenomena, and that this is unlikely to be mediated by T CD8 + lysis of APCs or other cells.

  • Immunodominance in tcd8 responses to viruses cell biology cellular immunology and mathematical models
    Immunity, 2004
    Co-Authors: Jonathan W Yewdell
    Abstract:

    Abstract Highlights from a Fundacion Juan March Interdisciplinary Meeting. CD8 + T cells (T CD8+ ) play a critical role in immunity to viruses. A central feature of antiviral T CD8+ responses is Immunodominance: out of thousands of potential target peptides, only a handful generate measurable responses. A recent Fundacion Juan March Meeting brought together scientists working on the various steps in antigen presentation and T cell biology that contribute to Immunodominance, whose understanding is key to rationally developing vaccines meant to elicit effective antiviral T CD8+ responses.

Davide Angeletti - One of the best experts on this subject based on the ideXlab platform.

  • Recombinant Influenza Vaccines: Saviors to Overcome Immunodominance
    Frontiers in Immunology, 2020
    Co-Authors: Nimitha R. Mathew, Davide Angeletti
    Abstract:

    It has been almost a decade since the 2009 influenza A virus pandemic hit the globe causing significant morbidity and mortality. Nonetheless, the annual influenza vaccination, which elicits antibodies mainly against the head region of influenza hemagglutinin (HA), remains as the mainstay to combat and reduce symptoms of influenza infection. Influenza HA is highly antigenically variable, thus limiting vaccine efficacy. Additionally, the HA head occupies the upper strata of the Immunodominance hierarchy thereby clouding the antibody response towards subdominant epitopes, which are usually conserved across different influenza strains. Isolation of monoclonal antibodies from individuals recognizing such epitopes has facilitated the development of recombinant vaccines that focus the adaptive immune response towards conserved, protective targets. Here we review some significant leaps in recombinant vaccine development, which could possibly help to overcome B cell and antibody Immunodominance and provide heterosubtypic immunity to influenza A virus.

  • outflanking Immunodominance to target subdominant broadly neutralizing epitopes
    Proceedings of the National Academy of Sciences of the United States of America, 2019
    Co-Authors: Davide Angeletti, Ivan Kosik, Jefferson J S Santos, William T Yewdell, Carolyn M Boudreau, Vamsee Aditya V Mallajosyula, Madeleine C Mankowski, Michael Chambers
    Abstract:

    A major obstacle to vaccination against antigenically variable viruses is skewing of antibody responses to variable immunodominant epitopes. For influenza virus hemagglutinin (HA), the Immunodominance of the variable head impairs responses to the highly conserved stem. Here, we show that head Immunodominance depends on the physical attachment of head to stem. Stem immunogenicity is enhanced by immunizing with stem-only constructs or by increasing local HA concentration in the draining lymph node. Surprisingly, coimmunization of full-length HA and stem alters stem-antibody class switching. Our findings delineate strategies for overcoming Immunodominance, with important implications for human vaccination.

  • Is It Possible to Develop a “Universal” Influenza Virus Vaccine? Outflanking Antibody Immunodominance on the Road to Universal Influenza Vaccination
    Cold Spring Harbor Perspectives in Biology, 2018
    Co-Authors: Davide Angeletti, Jonathan W Yewdell
    Abstract:

    Influenza remains a major human pathogen despite seasonal vaccination. At long last, there is energy and resources to develop influenza vaccines that provide more predictable and durable protection. Vaccines based on inducing antibodies to the conserved stem of the viral hemagglutinin (HA) have emerged as leading candidates for broadening population immunity and ultimately limiting antigenic drift. Here, we discuss the knowns and unknowns of HA-specific B-cell and antibody responses. In particular, we focus on how Immunodominance sculpts antibody responses and drives antigenic drift. We propose a number of strategies to overcome Immunodominance and improve the breadth and efficacy of antibody responses.

  • is it possible to develop a universal influenza virus vaccine outflanking antibody Immunodominance on the road to universal influenza vaccination
    Cold Spring Harbor Perspectives in Biology, 2018
    Co-Authors: Davide Angeletti, Jonathan W Yewdell
    Abstract:

    Influenza remains a major human pathogen despite seasonal vaccination. At long last, there is energy and resources to develop influenza vaccines that provide more predictable and durable protection. Vaccines based on inducing antibodies to the conserved stem of the viral hemagglutinin (HA) have emerged as leading candidates for broadening population immunity and ultimately limiting antigenic drift. Here, we discuss the knowns and unknowns of HA-specific B-cell and antibody responses. In particular, we focus on how Immunodominance sculpts antibody responses and drives antigenic drift. We propose a number of strategies to overcome Immunodominance and improve the breadth and efficacy of antibody responses.

  • outflanking Immunodominance to target subdominant broadly neutralizing epitopes
    bioRxiv, 2018
    Co-Authors: Davide Angeletti, Ivan Kosik, William T Yewdell, Carolyn M Boudreau, Vamsee Aditya V Mallajosyula, Michael Chambers, Madhu Prabhakaran, Heather D Hickman, Adrian B Mcdermott, Galit Alter
    Abstract:

    A major obstacle to vaccination to antigenically variable viruses is skewing of antibody responses to immunodominant epitopes. For influenza virus hemagglutinin (HA), the Immunodominance of the variable head impairs responses to the highly conserved stem. Here, we show that head Immunodominance depends on the physical attachment of head to stem. Stem immunogenicity is enhanced by immunizing with stem only-constructs or by increasing local HA concentration in the draining lymph node. Surprisingly, co-immunization of HA and stem alters stem-antibody class switching. Our findings delineate strategies for overcoming Immunodominance with important implications for human vaccination.

Henrik N Kloverpris - One of the best experts on this subject based on the ideXlab platform.

  • cd8 tcr bias and Immunodominance in hiv 1 infection
    Journal of Immunology, 2015
    Co-Authors: Henrik N Kloverpris, Reuben Mcgregor, James E Mclaren, Kristin Ladell, Mikkel Harndahl, Anette Stryhn, Jonathan M Carlson, Catherine Koofhethile
    Abstract:

    Immunodominance describes a phenomenon whereby the immune system consistently targets only a fraction of the available Ag pool derived from a given pathogen. In the case of CD8+ T cells, these constrained epitope-targeting patterns are linked to HLA class I expression and determine disease progression. Despite the biological importance of these predetermined response hierarchies, little is known about the factors that control Immunodominance in vivo. In this study, we conducted an extensive analysis of CD8+ T cell responses restricted by a single HLA class I molecule to evaluate the mechanisms that contribute to epitope-targeting frequency and antiviral efficacy in HIV-1 infection. A clear Immunodominance hierarchy was observed across 20 epitopes restricted by HLA-B*42:01, which is highly prevalent in populations of African origin. Moreover, in line with previous studies, Gag-specific responses and targeting breadth were associated with lower viral load set-points. However, peptide–HLA-B*42:01 binding affinity and stability were not significantly linked with targeting frequencies. Instead, Immunodominance correlated with epitope-specific usage of public TCRs, defined as amino acid residue–identical TRB sequences that occur in multiple individuals. Collectively, these results provide important insights into a potential link between shared TCR recruitment, Immunodominance, and antiviral efficacy in a major human infection.

  • hla specific intracellular epitope processing shapes an Immunodominance pattern for hla b 57 that is distinct from hla b 58 01
    Journal of Virology, 2013
    Co-Authors: Henrik N Kloverpris, Mikkel Harndahl, Anette Stryhn, Rebecca Payne, Greg J Towers, Fabian Chen, Lynn Riddell, Bruce D Walker
    Abstract:

    HLA-B*57 is strongly associated with immune control of HIV and delayed AIDS progression. The closely related, but less protective, HLA-B*58:01 presents similar epitopes, but HLA-B*58:01+ individuals do not generate CD8+ T cells targeting the KF11-Gag epitope, which has been linked to low viremia. Here we show that HLA-B*58:01 binds and presents KF11 peptide, but HIV-infected HLA-B*58:01+ cells fail to process KF11. This unexpected finding demonstrates that Immunodominance patterns can be influenced by intracellular events independent of HLA binding motifs.

Bruce D Walker - One of the best experts on this subject based on the ideXlab platform.

  • hla specific intracellular epitope processing shapes an Immunodominance pattern for hla b 57 that is distinct from hla b 58 01
    Journal of Virology, 2013
    Co-Authors: Henrik N Kloverpris, Mikkel Harndahl, Anette Stryhn, Rebecca Payne, Greg J Towers, Fabian Chen, Lynn Riddell, Bruce D Walker
    Abstract:

    HLA-B*57 is strongly associated with immune control of HIV and delayed AIDS progression. The closely related, but less protective, HLA-B*58:01 presents similar epitopes, but HLA-B*58:01+ individuals do not generate CD8+ T cells targeting the KF11-Gag epitope, which has been linked to low viremia. Here we show that HLA-B*58:01 binds and presents KF11 peptide, but HIV-infected HLA-B*58:01+ cells fail to process KF11. This unexpected finding demonstrates that Immunodominance patterns can be influenced by intracellular events independent of HLA binding motifs.

  • differential targeting and shifts in the Immunodominance of epstein barr virus specific cd8 and cd4 t cell responses during acute and persistent infection
    The Journal of Infectious Diseases, 2005
    Co-Authors: Tonia Woodberry, Nicole Frahm, Leah M Henry, Todd J Suscovich, Jennifer K Davis, Bruce D Walker, David T Scadden, Fred Wang, Christian Brander
    Abstract:

    The evolution of Epstein-Barr virus (EBV)-specific T cell responses that occurs during the acute and persistent stages of infection remains poorly characterized despite its importance for developing immune interventions for EBV-associated disorders. This study assessed T cell responses to 113 EBV-derived epitopes in 40 subjects with acute or persistent EBV infection. Although no significant differences were seen in the breadth of CD8 and CD4 T cell responses, their magnitude differed significantly over time; acutely infected subjects generated especially strong responses to lytic viral antigens. The cross-sectional shift in Immunodominance was also confirmed in subjects followed longitudinally from acute to persistent infection. In addition, human leukocyte antigen-matched siblings with discordant histories of symptomatic EBV infection showed no significant differences in their response patterns, suggesting that symptomatic EBV infection does not lead to unique persistent-stage responses. These data provide an assessment of Immunodominance patterns and guidance for developing immunotherapeutic interventions for EBV-associated disorders.

  • consistent patterns in the development and Immunodominance of human immunodeficiency virus type 1 hiv 1 specific cd8 t cell responses following acute hiv 1 infection
    Journal of Virology, 2002
    Co-Authors: Xu G Yu, Bruce D Walker, Marylyn M Addo, Eric S Rosenberg, William Rodriguez, Cecily A Fitzpatrick, Mary N Johnston, Daryld Strick, Philip J R Goulder, Marcus Altfeld
    Abstract:

    Human immunodeficiency virus type 1 (HIV-1)-specific CD8+ T-cell responses generated during acute infection play a critical role in the initial control of viremia. However, little is known about the viral T-cell epitopes targeted during acute infection or about their hierarchy in appearance and relative Immunodominance over time. In this study, HIV-1-specific CD8+ T-cell responses in 18 acutely infected individuals expressing HLA-A3 and/or -B7 were characterized. Detailed analysis of CD8 responses in one such person who underwent treatment of acute infection followed by reexposure to HIV-1 through supervised treatment interruptions (STI) revealed recognition of only two cytotoxic T-lymphocyte (CTL) epitopes during symptomatic acute infection. HIV-1-specific CD8+ T-cell responses broadened significantly during subsequent exposure to the virus, ultimately targeting 27 distinct CTL epitopes, including 15 different CTL epitopes restricted by a single HLA class I allele (HLA-A3). The same few peptides were consistently targeted in an additional 17 persons expressing HLA-A3 and/or -B7 during acute infection. These studies demonstrate a consistent pattern in the development of epitope-specific responses restricted by a single HLA allele during acute HIV-1 infection, as well as persistence of the initial pattern of Immunodominance during subsequent STI. In addition, they demonstrate that HIV-1-specific CD8+ T-cell responses can ultimately target a previously unexpected and unprecedented number of epitopes in a single infected individual, even though these are not detectable during the initial exposure to virus. These studies have important implications for vaccine design and evaluation.

Weisan Chen - One of the best experts on this subject based on the ideXlab platform.

  • Broad-Based CD4+ T Cell Responses to Influenza A Virus in a Healthy Individual Who Lacks Typical Immunodominance Hierarchy.
    Frontiers in Immunology, 2017
    Co-Authors: Li Chen, Anjaleena Anthony, Sara Oveissi, Miaojuan Huang, Damien Zanker, Kun Xiao, Chao Wu, Weisan Chen
    Abstract:

    Influenza A virus (IAV) infection is a significant cause of morbidity and mortality worldwide. CD4+ T cell responses have been shown to be important for influenza protection in mouse models and in human volunteers. IAV antigen-specific CD4+ T cell responses were found to focus on matrix 1 (M1) and nucleoprotein (NP) at the protein antigen level. At the epitope level, only several epitopes within M1 and NP were recognized by CD4+ T cells. And the epitope-specific CD4+ T cell responses showed a typical Immunodominance hierarchy in most of the healthy individuals studied. In this study, we reported one case of atypical Immunodominance hierarchy of CD4+ T cell responses to IAV. M1 and NP were still the immunodominant targets of CD4+ T cell responses. However, CD4+ T cell responses specific to eleven epitopes derived from M1 and NP were detected and showed no significant Immunodominance hierarchy. Such an atypical pattern is likely determined by the individual’s HLA alleles. These findings will help us better understand the anti-IAV immunity as a whole and improve future vaccines against IAV.

  • a virus specific cd8 t cell Immunodominance hierarchy determined by antigen dose and precursor frequencies
    Proceedings of the National Academy of Sciences of the United States of America, 2006
    Co-Authors: Nicole L La Gruta, Weisan Chen, Richard J. Webby, Katherine Kedzierska, Ken C Pang, Miles P Davenport, Stephen J Turner, Peter C. Doherty
    Abstract:

    Immunodominance hierarchies are a substantial, but poorly understood, characteristic of CD8+ T cell-mediated immunity. Factors influencing the differential responses to the influenza A virus nucleoprotein (NP366–374) and acid polymerase (PA224–233) peptides presented by H2Db have been analyzed by disabling (N5→ Q substitution) these peptides in their native configuration, then expressing them in the viral neuraminidase protein. This strategy of shifting epitopes within the same viral context resulted in an apparent equalization of DbNP366 [epitope consisting of viral nucleoprotein (NP) amino acid residues 366–374 complexed with the H2Db MHC class I glycoprotein] and DbPA224 (H2Db+PA224–233) epitope abundance after direct infection in vitro and induced reproducible changes in the magnitude of the DbNP366- and DbPA224-specific T cell subsets generated after infection of mice. Comparison of DbNP366- and Db PA224-specific CD8+ T cell responses induced from the native configuration and from the viral neuraminidase stalk demonstrated that the size of both primary and secondary responses is influenced by relative epitope levels and that, at least after secondary challenge, the magnitude of responses is also determined by CD8+ T cell precursor frequency. Thus, this Immunodominance hierarchy is a direct function of antigen dose and T cell numbers.

  • Immunodominance and immunodomination critical factors in developing effective cd8 t cell based cancer vaccines
    Advances in Cancer Research, 2006
    Co-Authors: Weisan Chen, James Mccluskey
    Abstract:

    The focusing of cellular immunity toward one, or just a few, antigenic determinant, even during immune responses to complex microorganisms or antigens, is known as Immunodominance. Although described in many systems, the mechanisms of determinant Immunodominance are only just beginning to be appreciated, especially in relation to the interplay between T cells of differing specificities and the interactions between T cells and the antigen‐presenting cells (APCs). The outcome of these cellular interactions can lead to a form of immune suppression of one specificity by another—described as “immunodomination”. The specific and detailed mechanisms involved in this process are now partly defined. A full understanding of all the factors that control Immunodominance and influence immunodomination will help us to develop better viral and cancer vaccines.

  • reversal in the Immunodominance hierarchy in secondary cd8 t cell responses to influenza a virus roles for cross presentation and lysis independent immunodomination
    Journal of Immunology, 2004
    Co-Authors: Weisan Chen, Jack R Bennink, Sameh Basta, Nektaria Dimopoulos, Ken C Pang, Kellyanne Masterman, Gina Kennedy, Felicita Hornung, Mark J Smyth, Jonathan W Yewdell
    Abstract:

    Immunodominance is a central feature of CD8 + T cell (T CD8 + ) responses to pathogens, transplants, and tumors. Determinants occupy a stable position in an Immunodominance hierarchy (α-, β-, etc.) defined by the frequencies of responding T CD8 + . In this paper, we study the mechanistic basis for place-swapping between α- (acid polymerase (PA) 224–233 ) and β-determinants (nuclear protein 366–374) in primary vs secondary anti-influenza A virus (IAV) responses in mice. This phenomena was recently correlated with the inability of IAV-infected nondendritic cells (DCs) to generate PA 224–233 , and it was proposed that secondary T CD8 + are principally activated by IAV-infected epithelial cells, while primary T CD8 + are activated by IAV-infected DCs. In this study, we show that the inability of non-DCs to generate PA 224–232 is relative rather than absolute, and that the preferential use of cross-priming in secondary anti-IAV responses can also account for the revised hierarchy. We further show that immunodomination of PA 224–233 -specific T CD8 + by nucleoprotein 366–374-specific T CD8 + plays a critical role in the phenomena, and that this is unlikely to be mediated by T CD8 + lysis of APCs or other cells.

  • heat aggregated noninfectious influenza virus induces a more balanced cd8 t lymphocyte Immunodominance hierarchy than infectious virus
    Journal of Virology, 2003
    Co-Authors: Sameh Basta, Weisan Chen, Jack R Bennink, Jonathan W Yewdell
    Abstract:

    CD8+-T-cell (TCD8+) responses to infectious viruses are characterized by an Immunodominance hierarchy in which the majority of TCD8+ respond to one or a few immunodominant determinants, with a minority of TCD8+ responding to a number of subdominant determinants. It is now well established that exogenous antigens are capable of inducing TCD8+ to such immunodominant determinants, but the diversity of the response and the nature of the Immunodominance hierarchy have not been examined. We addressed this issue by characterizing TCD8+ responses to influenza virus preparations rendered inert by incubation for 10 min at 100°C, as first reported by Speidel et al. (Eur. J. Immunol. 27:2391-2399, 1997). Extending these findings, we show that the primary TCD8+ response to boiled virus can be sufficiently robust to be detected ex vivo by intracellular cytokine staining and that the response encompasses many of the peptides recognized by TCD8+ induced by infectious virus. Importantly, the Immunodominance hierarchy elicited was leveled, and we were unable to detect TCD8+ that were specific for boiled virus. We used peritoneal exudate cells as antigen-presenting cells in vitro, and a number of observations indicated that boiled virus is processed via a phagocytic route that is likely to be endosomal in nature. These findings suggest that the repertoires of immunogenic peptides generated by endosomes and cytosolic processes overlap to a surprising degree. Furthermore, they demonstrate that the form of antigen administered can influence Immunodominance hierarchies and that exogenous-antigen vaccines can induce broad and balanced TCD8+ responses.