Abstract: T cells are central to the pathogenesis of systemic lupus erythematosus (SLE), however, little is known about how T cells function after infiltrating target organs. The current paradigm suggests that kidney infiltrating T cells (KITs) are highly activated effector cells contributing to tissue damage and ultimately organ failure. Here- in, we present preliminary data that KITs rather than being effector cells, express multiple inhibitory receptors and behave dysfunctionally, with reduced cytokine production and proliferative capacity that is driven by the expression of an “exhausted” transcriptional signature. Our data suggests that the tissue parenchyma has the capability to suppress T cell responses and limit damage to self. This proposal will allow us to expand on our novel finding that T cell exhaustion occurs in target organs in the setting of autoimmunity. The kinetics and generalizability of induction of T cell exhaustion in parenchymal organ targets of autoimmuni- ty remains unknown and will be explored in Aim 1. In Aim 2 we will examine tissue-specific factors that may be implicated in induction of T cell exhaustion. By targeting the parenchymal tissue rather than T cells, we may be able to identify novel therapeutic targets, which would not result in global immunosuppression. Finally in Aim 3 we will address whether T cell exhaustion is observed in human patients with SLE. While there is indirect ev- idence to suggest that this is the case, the studies we propose represent a direct approach to test whether T cell exhaustion occurs in SLE patients, and to assess the potential prognostic uses of markers of T cell exhaustion. This proposal will provide critical insights into how best to therapeutically promote tissue-resident T cell ex- haustion and thus protect target organs from damage. The long-term objective of this proposal is to improve patient care by identifying therapeutic targets and prog- nostic indicators for SLE patients. Exhausted cells differ metabolically and otherwise from activated T cells and thus might be selectively targeted, while limiting generalized immunosuppression. Completion of these aims will advance our knowledge in a newly emerging field and lay the groundwork for multiple future mechanistic, translational and clinical investigations.