Tissue resident memory T cells in glomerulonephritis
CD4+ T cells are central for the development of crescentic glomerulonephritis (GN). During GN, T cells are recruited to the kidney, however, the course and severity of GN might also be influenced by the pre-existing T cells resident in the kidney. In a mouse model of Staphylococcus aureus infection, we observe an extensive bacterial infection of the kidney which causes a profound renal accumulation of TH17 cells. After the clearance of infection, elevated amounts of T cells remain in the kidney and acquire a tissue resident memory T cell (TRM cell) phenotype. Induction of GN in this mouse model, after the mice recovered from infection, leads to aggravated renal disease and preliminary results indicate a reactivation of kidney resident TH17 cells previously generated during the Staphylococcus aureus infection. On the basis of these observations, we hypothesize that a renal infection causes persistent changes in TRM-cell composition in the kidney. During GN, infection-induced renal TRM cells are reactivated by inflammatory signals and alter course and severity of GN. In this project, we will focus on the characteristics and function of renal TRM cells in infection and autoimmunity. We will combine mouse infection models with models for GN to analyze the response of renal TRM cells in vivo. In parallel, the function of resident T cell populations will be investigated in human kidney biopsies. Main topics will be: i) phenotype, function, and transcriptomic profile of resident renal T cells; ii) signals that lead to reactivation of renal T cells; and iii) mechanisms by which resident T cells cause aggravated GN. In conclusion, this study will increase our knowledge on the contribution of T cells to GN and will help to identify processes that can be therapeutically targeted.
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