title: An exhaustion-like phenotype constrains the activity of CD4+ T cells specific for a self and melanoma antigen.
abstract: While the immune system has the capacity to recognize and destroy melanoma, tolerance mechanisms often hinder the development of effective anti-tumor immune responses. Since many melanoma antigens are self proteins expressed in normal melanocytes, self antigen exposure before tumor development can negatively impact the function of T cells specific for these self/tumor antigens. However, the contribution of self tolerance to anti-melanoma T cell dysfunction remains largely unexplored. We have previously described a TCR transgenic (Tg) mouse model in which T cells specific for the self/melanoma antigen, tyrosinase-related protein 1 (TRP1), develop in the presence of endogenous TRP1 expression (Ag+) and diminished antigen presentation due to the absence of gamma-interferon-inducible lysosomal thiol reductase (GILT-/-). We show that TRP1-specific T cells from these Ag+GILT-/-Tg mice do not protect from melanoma tumor growth, fail to induce autoimmune vitiligo, and undergo diminished proliferation compared to T cells from Ag-GILT+/+Tg mice. Despite an increased frequency of TRP1-specific Treg cells in Ag+GILT-/-Tg mice compared to Ag-GILT+/+Tg animals, Treg cell depletion only partially rescues the proliferative capacity of T cells from TRP1-expressing mice, suggesting the involvement of additional suppressive mechanisms. An increased percentage of melanoma-specific T cells from Ag+GILT-/-Tg animals express PD-1, an inhibitory receptor associated with the maintenance of T cell exhaustion. Antibody blockade of PD-1 partially improves the ability of TRP1-specific T cells from Ag+GILT-/-Tg mice to produce IL-2. These findings demonstrate that melanoma-specific T cells exposed to a self/melanoma antigen in healthy tissue develop an exhaustion-like phenotype characterized by PD-1-mediated immunosuppression prior to encounter with tumor.
authors: Department of Basic Medical Sciences, College of Medicine Phoenix, University of Arizona, Phoenix, Arizona, United States of America; Arizona Cancer Center, University of Arizona, Tucson, Arizona, United States of America.
authors: Matthew P
authors: MP
authors: Rausch
authors: Department of Basic Medical Sciences, College of Medicine Phoenix, University of Arizona, Phoenix, Arizona, United States of America; Arizona Cancer Center, University of Arizona, Tucson, Arizona, United States of America; Department of Immunobiology, College of Medicine, University of Arizona, Tucson, Arizona, United States of America.
authors: Karen Taraszka
authors: KT
authors: Hastings
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005434:Flow Cytometry; D007108:Immune Tolerance / Q000276:immunology; D016130:Immunophenotyping; D007376:Interleukin-2 / Q000276:immunology / Q000378:metabolism; D008297:Male; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology; D058950:Melanoma-Specific Antigens / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010088:Oxidoreductases / Q000235:genetics / Q000276:immunology; D050862:Oxidoreductases Acting on Sulfur Group Donors; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D014820:Vitiligo / Q000235:genetics / Q000276:immunology
chemical_list: D000951:Antigens, Neoplasm; D001324:Autoantigens; D007376:Interleukin-2; D058950:Melanoma-Specific Antigens; D008562:Membrane Glycoproteins; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D010088:Oxidoreductases; C079621:Tyrp1 protein, mouse; C483811:Ifi30 protein, mouse; D050862:Oxidoreductases Acting on Sulfur Group Donors