Characterization and function of regulatory T cells in glomerulonephritis

CD 4 + CD 25 + Foxp 3+调节性T细胞（Treg）对于维持外周耐受和预防自身免疫至关重要。如果自身免疫反应靶向肾脏，则可能发生肾小球肾炎（GN）。为了分析内源性T细胞调节GN的作用，我们使用了“调节性T细胞耗竭”（DEREG）小鼠，其在Foxp 3启动子的控制下表达白喉毒素（DTx）受体。在新月体肾小球肾炎的小鼠模型中，DTx注射后Treg耗竭加剧了Th 1应答，导致GN病程加重。有趣的是，肾炎DEREG小鼠中的Treg耗竭导致肾脏IL-10和PD-1表达增加。在该项目的第一部分中，将通过使用不同的转基因小鼠品系来鉴定肾组织中产生IL-10的细胞群，特别是在Treg耗竭后。候选细胞是CD 4 + Foxp 3- T细胞、树突细胞、巨噬细胞或调节性B细胞。在第二部分中，这些假定的抑制细胞的治疗潜力将通过过继细胞转移实验进行分析。最后，将分析共抑制分子如PD-1/PD-L1在肾毒性血清肾炎中的细胞表达和保护功能。目的是表征对治疗GN最有效的调节细胞亚群。

CD4+CD25+Foxp3+ regulatory T cells (Tregs) are of critical importance for the maintenance of peripheral tolerance and prevention of autoimmunity. If autoimmune responses target the kidney, glomerulonephritis (GN) may develop. To analyse the role of endogenous Tregs for regulation of GN, we used “depletion of regulatory T cell” (DEREG) mice which express the diphtheria toxin (DTx) receptor under control of the Foxp3 promoter. In a murine model of crescentic glomerulonephritis, Treg depletion upon DTx injection exacerbated the Th1 response and resulted in an aggravated course of GN. Interestingly, Treg depletion in nephritic DEREG mice resulted in an increased renal IL-10 and PD-1 expression. In the first part of the project, IL-10-producing cell populations in renal tissue, in particular following Treg depletion, will be identified by using different transgenic mouse strains. Candidate cells are CD4+Foxp3- T cells, dendritic cells, macrophages, or regulatory B cells. In the second part, the therapeutic potential of these putative suppressor cells will be analysed by adoptive cell transfer experiments. Finally, co-inhibitory molecules such as PD-1/PD-L1 will be analysed with respect to their cellular expression and protective function in nephrotoxic serum nephritis. The aim will be the characterization of the regulatory cell subpopulation which is most efficient for treatment of GN.