Bowen Hou, Yanyan Hu, Yuzhen Zhu, Xiaocui Wang, Wanyun Li, Jian Tang, Xian Jia, Jiayu Wang, Yu Cong, Minxue Quan, Hongying Yang, Haiping Zheng, Yuzhou Bao, Xiao Lei Chen, Hong-Rui Wang, Bing Xu, Nicholas R. J. Gascoigne, Guo Fu
{"title":"SHP-1 调控 CD8+ T 细胞效应器功能,但由于阶段特异性非冗余功能中继,它与 SHP-2 在 T 细胞衰竭中发挥着微妙的作用","authors":"Bowen Hou, Yanyan Hu, Yuzhen Zhu, Xiaocui Wang, Wanyun Li, Jian Tang, Xian Jia, Jiayu Wang, Yu Cong, Minxue Quan, Hongying Yang, Haiping Zheng, Yuzhou Bao, Xiao Lei Chen, Hong-Rui Wang, Bing Xu, Nicholas R. J. Gascoigne, Guo Fu","doi":"10.4049/jimmunol.2300462","DOIUrl":null,"url":null,"abstract":"<jats:title>Abstract</jats:title> SHP-1 (Src homology region 2 domain-containing phosphatase 1) is a well-known negative regulator of T cells, whereas its close homolog SHP-2 is the long-recognized main signaling mediator of the PD-1 inhibitory pathway. 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.","PeriodicalId":22698,"journal":{"name":"The Journal of Immunology","volume":"9 1","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2023-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"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\",\"authors\":\"Bowen Hou, Yanyan Hu, Yuzhen Zhu, Xiaocui Wang, Wanyun Li, Jian Tang, Xian Jia, Jiayu Wang, Yu Cong, Minxue Quan, Hongying Yang, Haiping Zheng, Yuzhou Bao, Xiao Lei Chen, Hong-Rui Wang, Bing Xu, Nicholas R. J. Gascoigne, Guo Fu\",\"doi\":\"10.4049/jimmunol.2300462\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<jats:title>Abstract</jats:title> SHP-1 (Src homology region 2 domain-containing phosphatase 1) is a well-known negative regulator of T cells, whereas its close homolog SHP-2 is the long-recognized main signaling mediator of the PD-1 inhibitory pathway. 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.\",\"PeriodicalId\":22698,\"journal\":{\"name\":\"The Journal of Immunology\",\"volume\":\"9 1\",\"pages\":\"\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2023-12-13\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"The Journal of Immunology\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.4049/jimmunol.2300462\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"The Journal of Immunology","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.4049/jimmunol.2300462","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
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
Abstract SHP-1 (Src homology region 2 domain-containing phosphatase 1) is a well-known negative regulator of T cells, whereas its close homolog SHP-2 is the long-recognized main signaling mediator of the PD-1 inhibitory pathway. 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.