Resident Memory T cells in Chronic Kidney Disease

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Project Summary Chronic kidney disease (CKD) is a disorder with significant morbidity and mortality which affects millions of Americans and shows no sign of improvement. Because there are no clinically approved therapeutics that can halt or reverse the progression of CKD to end stage kidney disease, research is needed to elucidate novel molecular and cellular targets. This project is based on the scientific premise that inflammation and fibrosis are key components in the progression of CKD. While recent research has highlighted the importance of the immune system in CKD, the specific contributions of resident memory T cells (TRMs) remain unknown. We have established and validated an aristolochic acid (AA)-induced mouse model of CKD which mimics clinical CKD. Five consecutive days of AA injections lead to a sustained decline in kidney function, indicated by reduced glomerular filtration rate and increased serum creatinine six weeks later. Flow cytometry of kidneys reveals a predominantly lymphocytic infiltrate within two weeks of the first AA injection, CD4 and CD8 T cells being the most abundant. These T cells persist for at least 6 weeks, coinciding with the persistent decline in kidney function. Moreover, a large population of T cells in the kidneys of these mice express pro-inflammatory and fibrotic cytokines, as well as CD103, a hallmark epithelial adhesion molecule of TRMs. TRMs have been described as contributors to unwanted inflammation in other chronic diseases and their presence has been descriptively noted in human kidneys. Thus, our central hypothesis is that TRMs mediate the progression of CKD through an inflammatory response that promotes kidney injury and fibrosis while inhibiting repair. The aims of this proposal will 1) determine the activation status and cytokine profiles of TRMs as well as their contributions to kidney inflammation and fibrosis; and 2) determine CD103’s necessity for T cell-epithelial adhesion and its regulation of T cell localization to injured kidneys, as well as its necessity for the TRM pro-inflammatory state. To achieve these goals, we will utilize genetic knockout models, adoptive immune cell transfer, flow cytometry, immunofluorescence microscopy, and pharmaceutical interventions both in vitro and in vivo. Successful execution of the proposed studies will illuminate basic mechanisms involved in CKD and could provide pre- clinical evidence for novel targets in the treatment of CKD. This is in line with the mission of the NIDDK, as this proposal focuses on the elucidation of treatments for progressive kidney disease. The laboratories of the sponsors along with their expertise in nephrology and immunology will provide an ideal training environment to carry out the proposed studies and advance the PI’s career. The training received will advance the knowledge, critical thinking, technical, and professional skills that will be required for the PI’s transition into independent academic research and establishment of his niche in the field of cardiorenal disease.