Background T cells play a significant role in the pathogenesis and end-organ damage observed in systemic lupus erythematosus (SLE). Previous studies using murine SLE models have demonstrated that kidney infiltrating T cells (KITs) differ substantially from their peripheral counterparts. Notably, KITs exhibit greater heterogeneity, characterized by a prominent population of resident memory and exhausted/dysfunctional T cells, along with a transitional or early exhausted population. In this study, our aim was to investigate T cell heterogeneity in multiple organs affected by SLE. We hypothesized that T cells isolated from different target organs would display distinct functional and transcriptional programs influenced by tissue-specific reprogramming. Additionally, we expected isolated clonal expansion in each target organ, with less clonal expansion in the spleen.

Methods Using the MRL. Fas^lpr model, which recapitulates numerous features human SLE, we isolated CD4 and CD8 T cells from five organs commonly impacted in SLE: kidney, liver, lung, spleen, and skin. T cells were obtained from female mice (18 wks or older) and male mice (26 wks or older). Single cell suspensions were prepared through chemical and mechanical dissociation. High-dimensional flow cytometry, metabolic analysis, functional studies, and scRNA-seq and TCR-seq were performed to analyze T cell heterogeneity.

Results Our findings revealed substantial variability in T cell function, metabolism, and phenotype across the different organs examined. Consistent with previous observations, the spleen was comprised of mainly effector T cells. Similar findings were observed in mucosal tissue associated infiltrating T cells isolated from lung and skin, which exhibited increased cytokine production, glucose uptake, and enhanced mitochondrial membrane potential. Conversely, T cells infiltrating solid organs such as the kidney and liver exhibited a more suppressed/exhausted phenotype, characterized by expression of exhaustion markers, an altered metabolic profile, and specific transcriptional program. Interestingly, clonal expansion was not organ-specific, as expanded clones were observed in all target organs.

Conclusion Our data underscore the influence of tissue parenchyma on the phenotype and transcriptional program of infiltrating immune cells. Specifically, solid organs (liver and kidney) possess the capacity to suppress T cell responses, potentially limiting self-damage. In contrast, T cells from lymphoid and mucosal tissues (skin and lung) exhibit a more activated phenotype. This dichotomy can be explained by the evolutionary need to minimize immune-mediated damage in solid organs while maintaining effective immunity against external infections in mucosal tissues. By gaining a deeper understanding of how immune cells are modulated within distinct tissue microenvironments, we may identify strategies to selectively target organ-specific manifestations while minimizing systemic immunosuppression.