Th45 - Autoreactive CD8+ T Cells are Restrained by an Exhaustion-like Program that is Maintained by LAG3

CD8⁺ T cell exhaustion is a differentiation state initiated by chronic high antigen stimulation, in which T cells become unresponsive to stimulation and lose effector function. Impaired chronic viral and tumor clearance has been attributed to CD8⁺ T cell exhaustion and can be partially reversed upon blockade of inhibitory receptors (IR) such as programmed cell death protein 1 (PD1). Despite detailed analysis of CD8⁺ T cell these models, a role an exhaustion program in autoimmunity is still not fully appreciated. The pancreatic islets are a site of chronic high antigen stimulation in Autoimmune Diabetes (AD). We therefore hypothesized that intra-islet CD8⁺ T cells are restrained by an exhaustion program that can be partially reversed by IR deletion. Using the Non-obese Diabetic mouse model of spontaneous AD, we show that intra-islet CD8⁺ T cells phenotypically, transcriptionally, epigenetically, and metabolically possess features of exhausted T cells, yet maintain key differences that may contribute to their persistent pathogenicity in AD. This “restrained” phenotype can be perturbed, and disease can be remarkably accelerated in the absence IR Lymphocyte Activating Gene 3 (LAG3). CD8⁺ T cell-restricted deletion of LAG3 promotes enhanced effector-like function and trafficking into the islets, while diminishing enrichment of an exhausted phenotype, revealing a previously underappreciated role for an exhaustion program in limiting autoimmunity. Single deletion of LAG3 from the surface of CD8⁺ T cells, strikingly alters the developmental state and pathogenicity of intra-islet CD8⁺ T cells, implicating LAG3 as a potential target for future autoimmune therapeutics.