Intra-islet CD8+T cells are restrained by an exhaustion program that can be reversed by LAG3 deletion

Abstract CD8+ T cell exhaustion or dysfunction is a differentiation state in which T cells become unresponsive to stimulation and lose effector function1. 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 in tumors and chronic viral infection, the role of the exhaustion program and the transcriptional networks that control CD8+T cell function and fate in autoimmunity are still unknown. Here we show that intra-islet CD8+T cells phenotypically and transcriptionally possess features of exhausted T cells, yet maintain key differences, such as an expanded repertoire of effector mechanisms, that contribute to their persistent pathogenicity in autoimmune diabetes. This dual identity, which we refer to as a ‘divergent’ exhaustion program, can be perturbed substantively by CD8+ T cell-restricted deletion of the IR Lymphocyte Activating Gene 3 (LAG3), causing enhanced effector-like function and pathogenicity. Understanding this divergent exhaustion program and its key mediators will guide future immunotherapeutic interventions by characterizing ways to promote exhaustion in autoimmunity and reversing exhaustion programs in chronic viral infections and tumors.