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.

点击翻译按钮获取中文摘要

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.