Contribution to the understanding of tolerance induction: The immunobiological impact of rapamycin on regulatory T cell function mediated by the chemokine homing receptor isoforms CXCR3-A and -B.

背景：外周归巢趋化因子受体CXCR 3的表达可在体内识别具有调节功能的CD 4+和CD 8 + T细胞（Treg）。CXCR 3-A和-B在TCR 4上的亚型表达以及它们对调节功能的生物学影响是未知的，假设：（1）CXCR 3-B亚型特异性配体CXCL 4和/或CXCL 10的结合介导TCR 4的调节功能。(2)mTOR抑制剂（雷帕霉素）选择性地促进CXCR 3+调节性T细胞的扩增和功能。总体目的：确定CXCR 3亚型信号传导对诱导调节功能的生物学影响，并阐明雷帕霉素或环孢素（CsA）是否干扰CXCR 3依赖性信号传导。 CXCR 3-A和/或-B同种型表达是否鉴定调节性T细胞。 CXCR 3-A和/或-B是否通过特异性配体激活介导CD 4 + CXCR 3 + T细胞的调节特性，并评估PI 3 K和MAPK激酶MEK/ERK、p38、p44/42信号传导在调节功能中的作用. 雷帕霉素和CsA对体外培养的人T细胞CXCR 3-A/B表达和亚型依赖性细胞内信号传导的影响. 目的：追踪肾移植受者外周血中CXCR 3 + T细胞的表达，预期结果：CXCR 3-A/B的表达可能介导CD 4 +T细胞的调节功能。mTOR抑制剂可能通过促进CXCR 3表达和信号传导而促进肾移植耐受。

Background: Expression of the peripheral homing chemokine receptor CXCR3 identifies CD4+ and CD8+ T cells with regulatory function (Tregs) in vivo. Isoform expression of CXCR3-A and -B on Tregs as well as their biological impact on regulatory function is unknown.Hypothesis: (1) Binding of the CXCR3-B-isoform specific ligands CXCL4 and/or CXCL10 mediate regulatory function of Tregs. (2) mTOR inhibitors (rapamycin) selectively promote expansion and function of CXCR3+ regulatory T cells.Overall aim: To determine the biological impact of CXCR3 isoform signaling on inducing regulatory function and to elucidate whether rapamycin or Cyclosporine (CsA) interfere with CXCR3 dependent signaling.Specific aims: To determine1. whether CXCR3-A and/or -B isoform expression identifies regulatory T cells.2. whether activation of CXCR3-A and/or -B via a specific ligand mediate regulatory properties of CD4+CXCR3+ T cells and to assess the role of PI3K and MAPK kinase MEK/ERK, p38, p44/42 signaling for regulatory function.3. the impact of rapamycin and CsA on CXCR3-A/B expression and isoform dependent intracellular signaling of human T cells in vitro.4. To trace CXCR3+Tregs in the recipient’s circulation after renal transplantation.Expected results: CXCR3-A/B expression might mediate regulatory properties of CD4+T cells. mTOR inhibitors might contribute to renal allograft tolerance by promoting CXCR3 expression and signaling.