Journal Article

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

Tabib, Tracy, Cardello, Carly, Lafyatis, Robert, Zhang, Qianxia, Lian, Christine G, Murphy, George F, Wherry, E. John, Cillo, Anthony R, Xiao, Hanxi, Workman, Creg J, Brunazzi, Erin A, Vignali, Dario A. A, Das, Jishnu, Grebinoski, Stephanie, Manne, Sasikanth

2022

Overview

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.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.

• Publisher: Nature Publishing Group
• Subject: Autoimmunity / CD8 antigen / Cell differentiation / Clonal deletion / Diabetes mellitus (insulin dependent) / Effector cells / Gene deletion / Genotype & phenotype / Immunotherapy / Lymphocytes / Lymphocytes T / Phenotypes / Receptor mechanisms / Tumors