Immunobiology of CD4+CD25+ T regulatory cells

描述(由申请人提供)：CD4+CD25+T调节(Treg)细胞的作用是通过抑制逃脱胸腺阴性选择的自身反应性成熟外周T细胞来抑制自身反应性的主要机制。尽管已经有能力证明这一免疫现象，但对控制Treg细胞发育、特异性、内稳态和功能的因素知之甚少。最近，我们实验室建立了一个关于Treg细胞的重要原理，即IL-2对Treg细胞的发育至关重要。重要的是，我们发现过继转移CD4+CD25+Treg细胞防止了IL-2Rbeta-/-小鼠快速而致命的自身免疫性疾病的发生，这种疾病伴随着大量的扩张，随后使用同基因或全异基因供者Treg细胞进行长期稳定的植入。这一结果表明Treg细胞在体内具有相当大的生长潜力。因此，该项目的一个主要目标是确定Treg细胞增殖和自稳的机制。 同种异体Tregs细胞预防自身免疫的有效性在开发利用Treg细胞进行过继免疫治疗的策略方面具有相当大的实用价值。此外，正如初步数据将显示的那样，许多Treg细胞是同种异体MHC的特异性细胞，因为这些细胞已经被选择在MHC不匹配的受体小鼠中扩增和存活。因此，原则上，TCR的特异性被定义为这些T细胞，即对MHC II类同种异体反应。因此，除了表征同种异体Tregs细胞的免疫抑制特性外，本提案的另一个主要目的是利用该模型系统和其他模型系统来研究TCR的特异性和多样性，因为它与Treg细胞的动态平衡和抑制活性有关。其具体目的是：1)进一步确定同种异体CD4+CD25vTreg细胞阻止IL-2Rbeta-/-小鼠自身免疫的基础；2)体内CD4+CD25+Treg细胞的生长和存活特征；以及3)测试限制TCR谱系的多样性对Treg细胞发育和功能的影响。

DESCRIPTION (provided by applicant): The action of CD4+CD25 + T regulatory (Treg) cells represents a major mechanism to inhibit self-reactivity by suppressing autoreactive mature peripheral T cells that have escaped thymic negative selection. In spite of the ready ability to demonstrate this immunological phenomenon, comparatively little is known concerning the factors controlling Treg cell development, specificity, homeostasis, and function. Recently, our laboratory established one important principle concerning Treg cells, namely that IL-2 is essential for their development. Importantly, we showed that the adoptive transfer of CD4+CD25+Treg cells prevented the onset of the rapid and lethal autoimmune disease in IL-2Rbeta -/- mice that was accompanied by substantial expansion, followed by long-term stable engraftment, using syngeneic or fully allogeneic donor Treg cells. This result makes plain that Treg cells have considerable growth potential in vivo. Therefore, one major objective of this project is to define the mechanism responsible for the proliferation and homoeostasis of Treg cells. The efficacy of allogeneic Tregs cells to prevent autoimmunity is of considerable practical value in developing strategies to utilize Treg cells in adoptive immunotherapy. Furthermore, as will be shown in the Preliminary Data, many Treg cells are specific for allogeneic MHC, as these cells have been selected to expand and survive in MHC-mismatched recipient mice. In principle, therefore, the TCR specificity is defined for these T reg cells, i.e. alloreactive to MHC class II. Thus, along with characterizing the immunosuppressive properties of allogeneic Tregs cells, the other major objective of this proposal is to utilize this and other model systems to investigate the specificity and diversity of the TCR as it relates to Treg cell homeostasis and suppressive activity. The specific aims are: 1) To further define the basis by which allogeneic CD4+CD25vTreg cells prevent autoimmunity in IL-2Rbeta-/- mice; 2) to characterize the growth and survival characteristics of CD4+CD25+Treg cells in vivo; and 3) to test the effect of limiting the diversity of the TCR repertoire on the development and function of Treg cells.