%0 Journal Article %J Nature Immunology %D 2019 %T PTPN2 regulates the generation of exhausted CD8+ T cell subpopulations and restrains tumor immunity %A LaFleur, MW %A Nguyen, TH %A Coxe, MA %A Miller, BC %A Yates, KB %A Gaudiano, EF %A Sen, DR %A Gillis, JE %A Al Abosy, R %A Freeman, G. J. %A Haining, WN %A Sharpe, A. H. %X

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.

PubMed DOI

%B Nature Immunology %V 20 %P 1335-1347 %G eng %N 10