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

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...

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Vydáno v:	Nature immunology Ročník 20; číslo 10; s. 1335 - 1347
Hlavní autoři:	LaFleur, Martin W., Nguyen, Thao H., Coxe, Matthew A., Miller, Brian C., Yates, Kathleen B., Gillis, Jacob E., Sen, Debattama R., Gaudiano, Emily F., Al Abosy, Rose, Freeman, Gordon J., Haining, W. Nicholas, Sharpe, Arlene H.
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	New York Nature Publishing Group US 01.10.2019 Nature Publishing Group
Témata:	631/250/1619 631/250/2152 631/250/251 631/250/255 631/250/580 Adenocarcinoma - immunology Animals Apoptosis Biomedical and Life Sciences Biomedicine Cancer Cancer immunotherapy CD8 antigen CD8-Positive T-Lymphocytes - physiology Cell death Cellular Senescence Chronic infection Clonal deletion Colonic Neoplasms - immunology Cytotoxicity Cytotoxicity, Immunologic Female Hepatitis A Virus Cellular Receptor 2 - metabolism Immune checkpoint Immune clearance Immune system Immune Tolerance Immunology Immunotherapy Immunotherapy - methods Infections Infectious Diseases Interferon Interferon Type I - metabolism Lymphocytes Lymphocytes T Lymphocytic Choriomeningitis - immunology Lymphocytic choriomeningitis virus - physiology Lymphoid Progenitor Cells - physiology Male Melanoma - immunology Melanoma, Experimental Mice Mice, Inbred C57BL Mice, Transgenic PD-1 protein Phosphatase Protein Tyrosine Phosphatase, Non-Receptor Type 2 - genetics Protein Tyrosine Phosphatase, Non-Receptor Type 2 - metabolism PTPN2 protein Signal Transduction Signaling Lymphocytic Activation Molecule Family - metabolism Skin Neoplasms - immunology Subpopulations Tumors
ISSN:	1529-2908, 1529-2916, 1529-2916
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Shrnutí:	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. 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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 M.W.L., W.N.H., and A.H.S. conceived the project and wrote the manuscript with assistance from T.H.N., M.A.C., B.C.M., E.F.G., J.E.G., and G.J.F.; M.W.L., T.H.N., W.N.H., and A.H.S. designed experiments; M.W.L. and T.H.N. performed and analyzed all experiments with assistance from M.A.C., J.E.G., and E.F.G.; K.B.Y. performed bulk RNA-seq sample processing and analyzed the RNA-seq data; B.C.M. and R.A. performed 10× single-cell RNA-seq sample processing and analyzed the single-cell RNA-seq data; D.R.S. performed ATAC-seq sample processing and analyzed the ATAC-seq data; G.J.F. contributed to αPD-1 experiments. Author Contributions
ISSN:	1529-2908 1529-2916 1529-2916
DOI:	10.1038/s41590-019-0480-4