Characterization and function of regulatory T cells in glomerulonephritis

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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.