Autoreactive CD8+ T cells are restrained by an exhaustion-like program that is maintained by LAG3

CD8+ T cell exhaustion is a distinct differentation state resulting from chronic antigen exposure and leading to hierarchical loss of effector functions. Using a murine model of diabetes, we show that CD8+ T cells derived from the islets of diabetic mice have CD8+ T cells that are canonically exhausted and yet retain sufficient effector function to contribute to pathogenicity in autoimmune diabetes. Genetic deletion of the inhibitory receptor LAG3 restricted to only CD8+ T cells lead to accelerated disease, with LAG3 deficient CD8+ T cells having enhanced effector function and trafficking. These findings reveal a distinct role of LAG3 in restraining autoreactive CD8+ T cells and implicate LAG3 as a potential therapeutic target in autoimmunity. NOD mice harboring a CD8+ T cell restricted genetic deletion of LAG3 were used to assess the role of LAG3 in autoimmune diabetes and were compared to control mice. CD8+ T cells were isolated from islets and lymph nodes by FACS. Bulk RNAseq, single-cell RNAseq with paired TCRseq, and single-cell ATACseq were performed on these isolated CD8+ T cells from control and LAG3 deleted mice. CD8+ T cells from three eight-week old female mice per group were pooled across two independent experiments for bulk RNAseq. CD8+ T cells from four eight-week old mice per group were used for scRNAseq experiments. CD8+ T cells from four eight-week old mice were used for scATACseq experiments.