Background/Purpose: While T cells are important for the pathogenesis of systemic lupus erythematosus (SLE) and lupus nephritis, little is known about how T cells function after infiltrating the kidney in the setting of organ damage. The current paradigm suggests that kidney infiltrating T cells (KITs) are activated effector cells contributing to tissue damage and ultimately organ failure. We aim to examine this hypothesis by directly examining KITs.

Methods: KITs and Splenic CD4⁺ and CD8⁺ T cells were isolated from diseased mice in 3 murine models of SLE (MRL/lpr, MRL.TLR9^-/- (fas sufficient), and FcγRIIB^-/-.Yaa). T cells were evaluated for phenotypic, functional, metabolic, and transcriptional profiles as noted in results.

Results: The majority of CD4⁺ and CD8⁺ KITs in all three murine lupus models are not effector cells, as hypothesized, but rather, KITs mimic the “exhausted” phenotype observed in tumor infiltrating T cells. KITs exhibited a significant increase in expression of multiple inhibitory receptors including PD-1, Lag3, and Tim3, and proved highly dysfunctional with reduced cytokine production and proliferative capacity.

Mechanistically this was linked directly to metabolic and specifically mitochondrial dysfunction. This phenotype is driven by the expression of an “exhausted” transcriptional signature.

Conclusion: KITs derived from lupus prone mice are exhibit a phenotypic and transcriptional signature that is analogous to what has been described in the setting of chronic infection and T cell infiltrates in the tumor microenvironment. Our data reveal that the tissue parenchyma has the capability to suppress T cell responses and limit damage to self. These findings may (1) lend insights into autoimmune related adverse events associated with cancer immunotherapy, which targets T cell exhaustion (2) open novel avenues for the treatment of autoimmunity based on selectively exploiting the exhausted phenotype of tissue-infiltrating T cells and (3) inform on pathophysiologic relationships between parenchymal tissues and infiltrating cells in numerous autoimmune disease states.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/examining-t-cell-exhaustion-in-murine-systemic-lupus-erythematosus/