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

Exhausted T cells are associated with inefficient viral clearance, tumor immunity and response to immunotherapy. Here the authors show CD8(+) T cells in the pancreatic islets have a LAG3-promoted 'restrained' phenotype resembling exhausted cells but maintain effector functions, and LAG3 expression limits pathology in the nonobese diabetic mouse model of type 1 diabetes. Impaired chronic viral and tumor clearance has been attributed to CD8(+) T cell exhaustion, a differentiation state in which T cells have reduced and altered effector function that can be partially reversed upon blockade of inhibitory receptors. The role of the exhaustion program and transcriptional networks that control CD8(+) T cell function and fate in autoimmunity is not clear. Here we show that intra-islet CD8(+) T cells phenotypically, transcriptionally, epigenetically and metabolically possess features of canonically exhausted T cells, yet maintain important differences. This 'restrained' phenotype can be perturbed and disease accelerated by CD8(+) T cell-restricted deletion of the inhibitory receptor lymphocyte activating gene 3 (LAG3). Mechanistically, LAG3-deficient CD8(+) T cells have enhanced effector-like functions, trafficking to the islets, and have a diminished exhausted phenotype, highlighting a physiological role for an exhaustion program in limiting autoimmunity and implicating LAG3 as a target for autoimmune therapy.