Immune-mediated diseases such as crescentic glomerulonephritis (cGN) are driven by inappropriately regulated cellular and humoral immune responses subsequently leading to the development of renal failure. However, mechanisms of immune regulation in cGN are less clear. In a mouse model of cGN, we have shown previously that Foxp3+ regulatory T cells (Tregs) suppress the pathogenic T-cell response by production of IL-10. Recently, we demonstrated that the co-inhibitory PD-1/PD-L1 pathway promotes Treg function during cGN, which is crucial to control the inflammatory Th1 immune response. Interestingly, preliminary data suggest that also inflammatory CD8+ T-cell responses are regulated by the PD-1/PD-L1 pathway during cGN. However, the phenotype, pathogenic relevance, biological function, and regulation of renal CD8+ T-cell responses in cGN are still incompletely understood. Moreover, we identified proximal tubular epithelial cells (PTECs) as a population of non-professional antigen-presenting cells (APCs) in the kidney that, in contrast to non-professional APCs from the liver, induce immunity rather than tolerance.
Thus, our studies will address the following aims:
1.) Phenotype and function of CD8+ T cells in murine models of acute and chronic kidney disease.
2.) Regulation of renal T-cell responses by targeting the co-inhibitory PD-1/PD-L1 pathway.
3.) Role of the co-inhibitory receptor TIGIT in the regulation of renal T-cell responses.
4.) Mechanisms of T-cell activation and regulation by non-professional APCs from kidney and liver.
5.) Phenotypic characterization of renal CD8+ T-cell subsets in cGN patients by single cell RNAseq and immunohistochemistry.
Our studies will result in a better understanding of mechanisms involved in the pathology and regulation of local inflammatory immune responses in acute and chronic kidney disease that may result in the identification of novel therapeutic targets in cGN.
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