In the classic paradigm of central tolerance, thymocytes with specificity for self-antigens are deleted during development, thereby leaving the peripheral T cell repertoire devoid of any cells capable of reacting to self-tissues. While the significance of this mechanism in preventing autoimmunity is well established, growing evidence indicates that many self-antigen specific T cells routinely escape deletion and populate the peripheral T cell repertoire without causing disease. This is especially likely in the case of tissue-restricted self-antigens that are poorly expressed in the thymus. How peripheral self-antigen specific T cells remain tolerant in the presence of their cognate antigen poses an intriguing question as these cells are likely involved in autoimmunity as well as anti-tumor immunity. Due to the severe limitations of monoclonal TCR transgenic T cell systems to accurately model complex polyclonal populations of antigen-specific T cells, several fundamental questions about self-antigen specific T cells remain unresolved. First, it is unclear to what extent central tolerance mechanisms such as clonal deletion and regulatory T cell (Treg) development play in the regulation of T cell reactivity to tissue-restricted self-antigens. Furthermore, it is unclear whether self-antigen specific conventional T cells (Tconv) present in the periphery are simply ignorant of their antigen, functionally anergic, or actively suppressed by Treg cells. We have developed powerful experimental systems involving peptide:MHC tetramer-based cell enrichment techniques and tissue-restricted antigen transgenic mice that allow us to directly characterize rare polyclonal populations of self-antigen specific T cells that naturally arise in endogenous repertoires. These tools will enable us to investigate these issues at an unprecedented level of physiological significance. We hypothesize that deletional tolerance of self-antigen specific T cells is far less extensive than previously appreciated, particularly in th case of tissue-restricted self-antigens, and accordingly, the peripheral repertoire of T cells is normally populated with numerous potentially self-reactive clones. We believe that self-antigen specific CD4+ T cells preferentially adopt a Treg lineage fate during development, and these cells suppress their Tconv counterparts in the periphery to establish tolerance within the overall self-antigen specific population. We will test this hypothesis by pursuing the following initial specific aims: 1) Determine how thymic selection shapes the peripheral repertoire of CD4+ T cells specific for tissue- restricted self-antigens, and 2) Determine how steady state tolerance is maintained in peripheral populations of self-antigen specific CD4+ T cells. The achievement of these aims will greatly improve our understanding of how non-deletional mechanisms of peripheral T cell tolerance are normally established for self-antigens in the steady state, and how we may exploit this information for therapeutic purposes.

Public Health Relevance

Autoimmune diseases collectively afflict as many as 50 million people in the U.S. alone, causing chronic and debilitating symptoms that create enormous social and economic burdens to society. This proposal investigates how the immune system controls potentially autoreactive T cells that normally exist in the body. The resulting findings will provide new insights into how immune tolerance to specific targets may eventually be manipulated to treat autoimmunity.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Transplantation, Tolerance, and Tumor Immunology Study Section (TTT)
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Ramachandra, Lakshmi
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Massachusetts General Hospital
United States
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Miller, Michelle L; McIntosh, Christine M; Williams, Jason B et al. (2018) Distinct Graft-Specific TCR Avidity Profiles during Acute Rejection and Tolerance. Cell Rep 24:2112-2126
Vandersarren, Lana; Bosteels, Cedric; Vanheerswynghels, Manon et al. (2017) Epitope mapping and kinetics of CD4 T cell immunity to pneumonia virus of mice in the C57BL/6 strain. Sci Rep 7:3472
Proekt, Irina; Miller, Corey N; Jeanne, Marion et al. (2016) LYN- and AIRE-mediated tolerance checkpoint defects synergize to trigger organ-specific autoimmunity. J Clin Invest 126:3758-3771
Young, J S; Chen, J; Miller, M L et al. (2016) Delayed Cytotoxic T Lymphocyte-Associated Protein 4-Immunoglobulin Treatment Reverses Ongoing Alloantibody Responses and Rescues Allografts From Acute Rejection. Am J Transplant 16:2312-23
Hondowicz, Brian D; An, Dowon; Schenkel, Jason M et al. (2016) Interleukin-2-Dependent Allergen-Specific Tissue-Resident Memory Cells Drive Asthma. Immunity 44:155-166
Legoux, Francois P; Lim, Jong-Baeck; Cauley, Andrew W et al. (2015) CD4+ T Cell Tolerance to Tissue-Restricted Self Antigens Is Mediated by Antigen-Specific Regulatory T Cells Rather Than Deletion. Immunity 43:896-908
Mattapallil, Mary J; Silver, Phyllis B; Cortes, Lizette M et al. (2015) Characterization of a New Epitope of IRBP That Induces Moderate to Severe Uveoretinitis in Mice With H-2b Haplotype. Invest Ophthalmol Vis Sci 56:5439-49
Scharschmidt, Tiffany C; Vasquez, Kimberly S; Truong, Hong-An et al. (2015) A Wave of Regulatory T Cells into Neonatal Skin Mediates Tolerance to Commensal Microbes. Immunity 43:1011-21
Moon, James J; Jenkins, Marc K (2015) The human T-cell repertoire grows up. Immunol Cell Biol 93:601-2
Nelson, Ryan W; Beisang, Daniel; Tubo, Noah J et al. (2015) T cell receptor cross-reactivity between similar foreign and self peptides influences naive cell population size and autoimmunity. Immunity 42:95-107