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However, recent studies have challenged the requirement of SHP-2 in PD-1 signaling, and follow-up studies further questioned the alternative idea that SHP-1 may replace SHP-2 in its absence. In this study, we systematically investigate the role of SHP-1 alone or jointly with SHP-2 in CD8+ T cells in a series of gene knockout mice. We show that although SHP-1 negatively regulates CD8+ T cell effector function during acute lymphocytic choriomeningitis virus (LCMV) infection, it is dispensable for CD8+ T cell exhaustion during chronic LCMV infection. Moreover, in contrast to the mortality of PD-1 knockout mice upon chronic LCMV infection, mice double deficient for SHP-1 and SHP-2 in CD8+ T cells survived without immunopathology. Importantly, CD8+ T cells lacking both phosphatases still differentiate into exhausted cells and respond to PD-1 blockade. Finally, we found that SHP-1 and SHP-2 suppressed effector CD8+ T cell expansion at the early and late stages, respectively, during chronic LCMV infection.<\/jats:p>","DOI":"10.4049\/jimmunol.2300462","type":"journal-article","created":{"date-parts":[[2023,12,13]],"date-time":"2023-12-13T14:52:40Z","timestamp":1702479160000},"page":"397-409","source":"Crossref","is-referenced-by-count":11,"title":["SHP-1 Regulates CD8+ T Cell Effector Function but Plays a Subtle Role with SHP-2 in T Cell Exhaustion Due to a Stage-Specific Nonredundant Functional Relay"],"prefix":"10.1093","volume":"212","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1974-8938","authenticated-orcid":false,"given":"Bowen","family":"Hou","sequence":"first","affiliation":[{"name":"State Key Laboratory of Cellular Stress Biology, School of Medicine, Faculty of Medicine and Life Sciences, Xiamen University , Xiamen ,","place":["China"]},{"name":"School of Life Sciences, Xiamen University , Xiamen 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Cellular Stress Biology, School of Medicine, Faculty of Medicine and Life Sciences, Xiamen University , Xiamen ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minxue","family":"Quan","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cellular Stress Biology, School of Medicine, Faculty of Medicine and Life Sciences, Xiamen University , Xiamen ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongying","family":"Yang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cellular Stress Biology, School of Medicine, Faculty of Medicine and Life Sciences, Xiamen University , Xiamen ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiping","family":"Zheng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cellular Stress Biology, School of Medicine, Faculty of Medicine and Life Sciences, Xiamen University , Xiamen 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,","place":["China"]},{"name":"Department of Hematology, The First Affiliated Hospital and Institute of Hematology, School of Medicine, Xiamen University , Xiamen ,","place":["China"]},{"name":"Cancer Research Center of Xiamen University , Xiamen ,","place":["China"]},{"name":"Laboratory Animal Center, Xiamen University ; Xiamen ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,12,13]]},"reference":[{"key":"2025020405440187500_r1","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.immuni.2011.07.010","article-title":"CD8+ T cells: foot soldiers of the immune system","volume":"35","author":"Zhang","year":"2011","journal-title":"Immunity"},{"key":"2025020405440187500_r2","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1016\/j.immuni.2007.08.007","article-title":"Heterogeneity and cell-fate decisions in effector and memory CD8+ T cell differentiation during viral 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