CTLA4Ig/VISTAIg combination therapy selectively induces CD4(+) T cell-mediated immune tolerance by targeting the SOCS1 signaling pathway in porcine islet xenotransplantation

作者全名："Wang, Dan; Bai, Xue; Wang, Bin; Yi, Qiying; Yu, Weihua; Zhang, Xinying; Tian, Ruoyuan; Zhang, Xiao; Li, Caihua; Chen, Yi; Liu, Yang; Cheng, Yao; He, Sirong"

作者地址："[Wang, Dan; Bai, Xue; Zhang, Xinying; Tian, Ruoyuan; Zhang, Xiao; Li, Caihua; Chen, Yi; Liu, Yang; He, Sirong] Chongqing Med Univ, Coll Basic Med, Dept Immunol, 1 Yixueyuan Rd, Chongqing 400016, Peoples R China; [Wang, Dan] Chongqing Med Univ, Affiliated Hosp 1, Dept Resp & Crit Care Med, Chongqing, Peoples R China; [Bai, Xue; Zhang, Xinying; Tian, Ruoyuan; Zhang, Xiao; Li, Caihua; Chen, Yi; Liu, Yang; He, Sirong] Chongqing Med Univ, Coll Basic Med, Chongqing Key Lab Basic & Translat Res Tumor Immu, Chongqing, Peoples R China; [Wang, Bin] Chongqing Med Univ, Inst Life Sci, Chongqing, Peoples R China; [Yi, Qiying] Chongqing Med Univ, Lab Anim Ctr, Chongqing, Peoples R China; [Yu, Weihua] Chongqing Med Univ, Inst Neurosci, Chongqing, Peoples R China; [Cheng, Yao] Chongqing Med Univ, Affiliated Hosp 2, Dept Hepatobiliary Surg, Chongqing, Peoples R China"

通信作者："Cheng, Y; He, SR (通讯作者)，Chongqing Med Univ, Coll Basic Med, Dept Immunol, 1 Yixueyuan Rd, Chongqing 400016, Peoples R China."

来源：IMMUNOLOGY

ESI学科分类：IMMUNOLOGY

WOS号：WOS:000769998700001

JCR分区：Q2

影响因子：6.4

年份：2022

卷号：166

期号：2

开始页：169

结束页：184

文献类型：Article

关键词：combination therapy; immune checkpoint; immune tolerance; porcine islet xenotransplantation

摘要："T cell inhibitory receptors can regulate the proliferation or function of T cells by binding to their ligands and present a unique opportunity to manage destructive immune responses during porcine islet xenotransplantation. We applied ex vivo porcine islet xenotransplantation and in vitro mixed lymphocyte-islet reaction models to assess immune checkpoint receptor expression profiles in recipient T cells, investigated whether CTLA4 or VISTA immunoglobulin (Ig) combination therapy alone could suppress porcine islet xenograft rejection and further analyzed its potential immune tolerance mechanism. Recipient T cells expressed moderate to high levels of CTLA4, PD-1, TIGIT and VISTA, and the frequency of CTLA4(+)CD4(+), TIGIT(+)CD4(+), VISTA(+)CD4(+) and VISTA(+)CD8(+) T cells was positively correlated with porcine islet xenograft survival time in xenotransplant recipients. Combined treatment with CTLA4Ig and VISTAIg selectively inhibited recipient CD4(+) T cell hyper-responsiveness and proinflammatory cytokine production and significantly delayed xenograft rejection. SOCS1 deficiency in CD4(+) T cells stimulated by xenogeneic islets facilitated hyper-responsiveness and abolished the suppressive effect of combination therapy on recipient T cell-mediated porcine islet damage in vivo and in vitro. Further mechanistic studies revealed that combined treatment significantly induced SOCS1 expression and inhibited the Jak-STAT signalling pathway in wild-type recipient CD4(+) T cells stimulated by xenogeneic islets, whereas SOCS1 deficiency resulted in Jak-STAT signalling pathway activation in recipient CD4(+) T cells. We demonstrated a major role for CTLA4 and VISTA as key targets in CD4(+) T cell hyper-responsiveness and porcine islet xenograft rejection. The selective inhibition of CD4(+) T cell immunity by CTLA4Ig/VISTAIg is based on SOCS1-dependent signalling."

基金机构：Kuanren Talents Program of the second affiliated hospital of Chongqing Medical University [KY2019Y002]; Science and Technology Research Program of Chongqing Municipal Education

基金资助正文："the Kuanren Talents Program of the second affiliated hospital of Chongqing Medical University, Grant/Award Number: KY2019Y002; the Science and Technology Research Program of Chongqing Municipal Education"