PTPN2 regulates the generation of exhausted CD8+ T cell subpopulations and restrains tumor immunity

Autor: Kathleen B. Yates, W. Nicholas Haining, Thao H. Nguyen, Rose Al Abosy, Debattama R. Sen, Arlene H. Sharpe, Gordon J. Freeman, Matthew A. Coxe, Jacob E. Gillis, Emily F. Gaudiano, Brian C. Miller, Martin W. LaFleur
Rok vydání: 2019
Předmět:
Zdroj: Nature Immunology. 20:1335-1347
ISSN: 1529-2916
1529-2908
DOI: 10.1038/s41590-019-0480-4
Popis: CD8+ T cell exhaustion is a state of dysfunction acquired in chronic viral infection and cancer, characterized by the formation of Slamf6+ progenitor exhausted and Tim-3+ terminally exhausted subpopulations through unknown mechanisms. Here we establish the phosphatase PTPN2 as a new regulator of the differentiation of the terminally exhausted subpopulation that functions by attenuating type 1 interferon signaling. Deletion of Ptpn2 in CD8+ T cells increased the generation, proliferative capacity and cytotoxicity of Tim-3+ cells without altering Slamf6+ numbers during lymphocytic choriomeningitis virus clone 13 infection. Likewise, Ptpn2 deletion in CD8+ T cells enhanced Tim-3+ anti-tumor responses and improved tumor control. Deletion of Ptpn2 throughout the immune system resulted in MC38 tumor clearance and improved programmed cell death-1 checkpoint blockade responses to B16 tumors. Our results indicate that increasing the number of cytotoxic Tim-3+CD8+ T cells can promote effective anti-tumor immunity and implicate PTPN2 in immune cells as an attractive cancer immunotherapy target.
Databáze: OpenAIRE
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