CD8+CD122+PD1+ 调节性T细胞诱导免疫耐受及其免疫调节机制

器官移植和自身免疫疾病病人需要持续使用免疫抑制剂治疗，但是长期治疗易引起严重的副作用。短期使用免疫调节性T细胞（CD4+CD25+Treg)诱导免疫耐受以抑制移植排斥或自身免疫是最理想治疗方案，但其在正常动物受体的抑制效果有限。我们的最新研究表明CD8+CD122+Treg比CD4+CD25+Treg能更有效地抑制传统T淋巴细胞的增殖, 并能在免疫缺陷小鼠模型更显著地推迟同种异体移植物的排斥，提示前者更有潜在的应用价值。此外,我们的初步研究首次显示经体外抗原特异性扩容后的CD8+CD122+PD1+Treg还能推迟正常小鼠受体对移植物的排斥。因此，我们将在本项目中进一步采用能抵制自身细胞凋亡的Treg（内因）和联合使用小剂量免疫抑制剂（外因）的新策略,以提高该Treg的抑制效果和诱导免疫耐受，并进一步研究该Treg的免疫调节作用机制,为设计更有效的抑制移植排斥的临床试验方案提供理论依据。

A patient with a transplanted oragn or autoimmune disease needs continuous immunosuppressive treaments , which cause serious side effects including infections and tumors. Induction of immune tolerance to an allograft or autoantigen without continuous immunosuppression is a highly desired goal in the field of transplantation and immunology. CD4+CD25+ Tregs have been extensively studied and utilized to promote allograft survival, inhibit autoimmune diseases and induce immune tolerance. However, their potential applications in clinical transplantation are limited due to their inability to prolong allograft survival in normal wide-type animals after their adoptive transfer. Hence it is compelling to search for more effective Tregs. Our recent studies have shown that CD8+CD122+ Tregs are more potent in suppression of conventional T cell proliferation in vitro and inhibition of allograft rejection in Rag1-/- mouse models than their CD4+CD25+ counterparts. We also found that CD8+CD122+ Tregs underwent faster homeostatic proliferation in vivo than CD4+CD25+ Tregs. Moreover, our preliminary data have demonstrated that in vitro-expanded CD8+CD122+PD1+ Tregs by donor antigens are even capable of delaying allograft rejection in wide-type mice. These findings suggest that CD8+CD122+ Tregs may be more valuable in clinical applications than their CD4+CD25+ counterparts. Based on these novel findings, we therefore propose to explore the new strategies of inducing long-term allograft survival or tolerance by adoptive transfer of the CD8+CD122+PD1+ Tregs. We will seek to significantly enhance their efficacy in suppression in normal recipient mice using apoptosis-resistant CD8+CD122+PD1+ Tregs or via combining the Treg transfers with low doses of immunosuppressive agents for short-term. Both measures are designed to promote the Treg strength for the induction of long-term allograft survival or tolerance in wild-type mice. Finally, we will propose to study the mechanisms by which these Tregs exert their suppression. Understanding their mechanisms of action would provide new insight into designing highly effective approaches to enhancing their suppression of allograft rejection. In these studies, neutralizing antibodies and gene-deficient mice will be utilized to study their mechanisms of action. Murine skin and islet transplant models will be employed to study Treg suppression of allograft rejection. Completion of the proposed studies, therefore, has important clinical implications.