The project described in this application addresses a mechanistic study aimed at understanding the steps involved in generation of immunodominant epitopes. Immunodominance is a phenomenon that has long been recognized but yet remains unclear to date. It is well known that the immune system focuses on and responds to very few representative epitopes (referred to as immunodominant epitopes) from invading pathogenic insults ranging from such as infectious agents and, antigenic targets in autoimmune diseases, allergy, and cancer. In each all these cases, the immune system either responds positively or fails to respond to antigenic peptides in the context of MHC molecules. Recent advances in our understanding of the antigen presentation pathway have shown that the steps of antigen processing and selection critically influence the peptide repertoire presented to T-cells. Recently, we have made considerable progress in developing a reductionist antigen processing system for MHC class II molecules that utilizes five purified protein components of the class II antigen presentation pathway. Notably, this system yielded physiologically relevant immunodominant epitopes restricted to HLA-DR1. In this proposal, we will extend this MHC II system to another MHC class II molecules HLA-DR4 and would explore steps involved in epitope capture and antigen processing. Overall, we propose to dissect underlying factors of T-cell immunodominance.
Aim 1 would explore the temporal relationship between antigen capture and processing.
In Aim 2, we would investigate epitope hierarchy and the role for DM, and in Aim 3, we would analyze contributions of HLA-DO to epitope capture and editing. Hence, knowledge of the identity of immunodominant epitopes, and a clear understanding of how they are generated inside cells, can guide the design of effective immunotherapeutics.
Development of effective vaccines and rational design of therapeutics for intervention in autoimmune diseases or cancer rely on good knowledge of key regions on a pathogen, or proteins from cancer cells or self that can be targeted by the immune system and are generally called antigenic epitopes. The immune system recognizes these epitopes and mounts specific responses through its cellular components, T cells and B cells. The specific cells become activated and fight the infection and then can retain the memory of the pathogen for future attacks (memory cells). Our study outlined in this proposal addresses understanding of the pathways that physiologically relevant antigenic epitopes are selected by the immune system. Our hypothesis in this application is based on strong preliminary data generated by a robust novel technology developed by our laboratory. Because of its unique minimalist nature, it can efficiently dissect steps involved in processing of antigens and their presentation to the T cells. We believe that our findings would change our current view on selection of antigenic epitopes. By knowing steps involved in immune epitope capture and its processing, investigators can design biologics that are intelligently based and therefore can be highly effective while avoiding nonspecific side effects.
|Darrah, Erika; Kim, AeRyon; Zhang, Xi et al. (2016) Proteolysis by Granzyme B Enhances Presentation of Autoantigenic Peptidylarginine Deiminase 4 Epitopes in Rheumatoid Arthritis. J Proteome Res :|
|Kim, AeRyon; Sadegh-Nasseri, Scheherazade (2015) Determinants of immunodominance for CD4 T cells. Curr Opin Immunol 34:9-15|
|Sadegh-Nasseri, Scheherazade; Kim, AeRyon (2015) Exogenous antigens bind MHC class II first, and are processed by cathepsins later. Mol Immunol 68:81-4|
|Kim, AeRyon; Hartman, Isamu Z; Poore, Brad et al. (2014) Divergent paths for the selection of immunodominant epitopes from distinct antigenic sources. Nat Commun 5:5369|
|Kim, Tae Hyung; Swierczewska, Magdalena; Oh, Yumin et al. (2013) Mix to validate: a facile, reversible PEGylation for fast screening of potential therapeutic proteins in vivo. Angew Chem Int Ed Engl 52:6880-4|
|Poluektov, Yuri O; Kim, Aeryon; Hartman, Isamu Z et al. (2013) HLA-DO as the optimizer of epitope selection for MHC class II antigen presentation. PLoS One 8:e71228|
|Sadegh-Nasseri, Scheherazade; Chou, Chih-Ling; Hartman, Isamu Z et al. (2012) How HLA-DM works: recognition of MHC II conformational heterogeneity. Front Biosci (Schol Ed) 4:1325-32|
|Dalai, Sarat K; Khoruzhenko, Stanislav; Drake, Charles G et al. (2011) Resolution of infection promotes a state of dormancy and long survival of CD4 memory T cells. Immunol Cell Biol 89:870-81|
|Sadegh-Nasseri, Scheherazade; Natarajan, Sateesh; Chou, Chih-Ling et al. (2010) Conformational heterogeneity of MHC class II induced upon binding to different peptides is a key regulator in antigen presentation and epitope selection. Immunol Res 47:56-64|
|Hartman, Isamu Z; Kim, AeRyon; Cotter, Robert J et al. (2010) A reductionist cell-free major histocompatibility complex class II antigen processing system identifies immunodominant epitopes. Nat Med 16:1333-40|
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