As a limitation of our study, it should be acknowledged that the NOH model only partially replicates (acute) interstitial nephritis. advent of immune-checkpoint inhibitors has led to a reappraisal of the role of T cells in renal immunology. However, it remains elusive how T cells with specificity for renal autoantigens are activated and participate in immune-mediated nephritis. Here, we followed the fate and function of pathogen-activated autoreactive CD8 T cells that are specific for a renal autoantigen. We demonstrate that recently activated splenic CD8 T cells developed a hybrid phenotype in the context of renal autoantigen cross-presentation, combining hallmarks of activation and T cell dysfunction. While circulating memory T cells rapidly disappeared, tissue-resident memory T cells emerged and persisted within the kidney, orchestrating immune-mediated nephritis. Notably, T cells infiltrating kidneys of patients with interstitial nephritis also expressed key markers of tissue residency. This study unveils how a tissue-specific immune response can dissociate from its systemic counterpart driving a compartmentalized immune response in the kidneys of mice and man. Consequently, targeting tissue-resident memory T cells emerges as a promising strategy to control immune-mediated kidney disease. Keywords: T cell response, Tissue residency, Renal autoimmunity, Nephritis, CD8 Subject terms: Autoimmunity, Cytotoxic T cells, Lymphocyte differentiation Introduction Immune-mediated nephritis results from an inappropriate immune response against self-antigens or innocuous substances (e.g., antibiotics). It can cause renal function decline up to end-stage renal disease. To date, a substantial body of knowledge exists regarding antibody-mediated forms of immune-mediated nephritis [1]. In contrast, the role of cellular immunity in the context of immune-mediated kidney disease lacks understanding, even though infiltrates of various immune cells are regularly present in biopsies of affected kidneys. Additionally, the density and composition of inflammatory infiltrates correlate with the deterioration of renal function [2]. Thus, there is a pressing need to decipher cellular immunity in the kidney. Cytotoxic CD8+ T lymphocytes (CTLs) represent one of the most abundant immune cell types within renal infiltrates and there is strong evidence that antigen-specific CTLs play a pivotal role in various entities of immune-mediated nephritis [3]. CTL infiltrates are particularly common in forms of interstitial nephritis (e.g., drug-induced acute interstitial nephritis [AIN] or immune-checkpoint inhibitor [ICI]-related nephritis) and can be found in Y16 15C27% of renal biopsies performed for acute kidney injury [4]. Moreover, various infections or systemic auto-immune diseases can also be associated with interstitial nephritis [5]. Intriguingly, only a minority of patients treated with a particular drug develop AIN, indicative of a continuous and active regulation of local immune responses in the kidney protecting its structural integrity. Similar to the gut, the kidney is constantly exposed to xenobiotic products, which it removes from the circulation. It therefore must balance immune responses to innocuous or self-antigens and pathogens. Hence, CTL-driven immune-mediated disease occurs if central or peripheral tolerance mechanisms fail to protect the host from a self-targeted immune response. The high incidence of immune-mediated nephritis following ICI therapy for malignant disease further underlines the importance of peripheral tolerance mechanisms in protecting the kidneys from autoreactive T cells [6]. Nevertheless, the details of underlying molecular programs defining and controlling this autoreactive state, as well as the complex mechanisms of activation, differentiation, and memory formation of autoreactive CTLs are not well understood. Since nephritis involves a primarily Y16 localized immune response, the question arises how local immunity is initiated and maintained in the kidney over time. This also involves the issue of how CTLs that are situated in the interstitium of the kidney gain access to their cognate antigen after its passage through the nephron, from which they are separated by a layer of epithelial cells. Tissue-resident memory T (TRM) cells are a potential culprit as they are a local memory population that stably resides in the tissue over time and has been identified in various organs, including the kidneys [7]. TRM cell differentiation is essential in accelerating local pathogen control [8]. However, it is unclear to what extent they also contribute to inducing Y16 and maintaining renal autoimmunity [9]. Although, Y16 several murine models (e.g., transgenic lupus nephritis, pauci-immune nephritis, immunoglobulin A nephritis, or nephrotoxic nephritis models) have been established to study auto-immune kidney disease, none of Nos3 these models focuses on the cellular immune response in the kidney [10C13]. Hence, studying details of CTL-driven renal autoimmunity relies on the establishment of novel preclinical models. In this study, we present a new mouse model for cellular autoimmunity.