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避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，但相对而言，关于控制Treg细胞发育、特异性、稳态和功能的因素知之甚少。最近，我们的实验室建立了一个关于Treg细胞的重要原理，即IL-2对其发育至关重要。重要的是，我们发现CD4+CD25+Treg细胞的过继转移可以防止IL-2Rbeta -/-小鼠快速和致命的自身免疫性疾病的发生，这种疾病伴随着大量扩增，随后是长期稳定的移植，使用同基因或完全异体供体Treg细胞。这一结果说明Treg细胞在体内具有相当大的生长潜力。因此，本项目的一个主要目标是确定Treg细胞增殖和稳态的机制。

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.