An exhaustion-like phenotype constrains the activity of CD4+ T cells specific for a self and melanoma antigen

Matthew P. Rausch, Karen Taraszka Hastings

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere0123332
JournalPLoS One
Volume10
Issue number4
DOIs
StatePublished - Apr 15 2015

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Melanoma-Specific Antigens
T-cells
Autoantigens
melanoma
T-lymphocytes
antigens
T-Lymphocytes
Phenotype
phenotype
Melanoma
Transgenic Mice
genetically modified organisms
Tumors
neoplasms
mice
proteins
transgenic animals
Genetically Modified Animals
Regulatory T-Lymphocytes
Programmed Cell Death 1 Receptor

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

An exhaustion-like phenotype constrains the activity of CD4+ T cells specific for a self and melanoma antigen. / Rausch, Matthew P.; Hastings, Karen Taraszka.

In: PLoS One, Vol. 10, No. 4, e0123332, 15.04.2015.

Research output: Contribution to journalArticle

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