학술논문
PTPN2 regulates the generation of exhausted CD8.sup.+ T cell subpopulations and restrains tumor immunity
Document Type
Report
Author
Source
Nature Immunology. October 2019, Vol. 20 Issue 10, p1335, 13 p.
Subject
Language
English
ISSN
1529-2908
Abstract
Author(s): Martin W. LaFleur [sup.1] [sup.2] [sup.3] [sup.4] , Thao H. Nguyen [sup.1] [sup.3] , Matthew A. Coxe [sup.1] [sup.3] , Brian C. Miller [sup.1] [sup.2] [sup.3] [sup.5] [sup.6] , [...]
CD8.sup.+ T cell exhaustion is a state of dysfunction acquired in chronic viral infection and cancer, characterized by the formation of Slamf6.sup.+ progenitor exhausted and Tim-3.sup.+ 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.sup.+ T cells increased the generation, proliferative capacity and cytotoxicity of Tim-3.sup.+ cells without altering Slamf6.sup.+ numbers during lymphocytic choriomeningitis virus clone 13 infection. Likewise, Ptpn2 deletion in CD8.sup.+ T cells enhanced Tim-3.sup.+ 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.sup.+CD8.sup.+ T cells can promote effective anti-tumor immunity and implicate PTPN2 in immune cells as an attractive cancer immunotherapy target. Exhaustion is an acquired state of T cell dysfunction. Sharpe and colleagues demonstrate that the phosphatase PTPN2 supports a T cell-intrinsic exhaustion program in both chronic infection and cancer models.
CD8.sup.+ T cell exhaustion is a state of dysfunction acquired in chronic viral infection and cancer, characterized by the formation of Slamf6.sup.+ progenitor exhausted and Tim-3.sup.+ 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.sup.+ T cells increased the generation, proliferative capacity and cytotoxicity of Tim-3.sup.+ cells without altering Slamf6.sup.+ numbers during lymphocytic choriomeningitis virus clone 13 infection. Likewise, Ptpn2 deletion in CD8.sup.+ T cells enhanced Tim-3.sup.+ 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.sup.+CD8.sup.+ T cells can promote effective anti-tumor immunity and implicate PTPN2 in immune cells as an attractive cancer immunotherapy target. Exhaustion is an acquired state of T cell dysfunction. Sharpe and colleagues demonstrate that the phosphatase PTPN2 supports a T cell-intrinsic exhaustion program in both chronic infection and cancer models.