Using the autoimmune type 1 diabetes NOD mouse model, Grebinoski and Zhang et al. showed that intra-islet CD8+ T cells comprised a heterogeneous population that sustained phenotypic, functional, transcriptional, metabolic, and epigenetic changes, and over time, accumulated a PD1+TCF1-TOX+CD8+ Tex cell-like subpopulation of “restrained” autoreactive effectors. CD8+ T cell-selective deficiency of cell surface expression of the inhibitor LAG3 accelerated NOD diabetes, which was characterized by more polyfunctional, effector-like, intra-islet CD8+ T cells with a higher frequency of expanded and more unique TCR clones, suggestive of epitope spreading.
Contributed by Paula Hochman
ABSTRACT: 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.
Author Info: (1) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Graduate Program of Microbiology and Immunology, University of Pittsburgh School of
Author Info: (1) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Graduate Program of Microbiology and Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. (2) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Graduate Program of Microbiology and Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. Program in Cellular and Molecular Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA. (3) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. (4) Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. (5) Center for Systems Immunology, Departments of Immunology and Computational & Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. CMU-Pitt Joint Computational Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. (6) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. (7) Division of Rheumatology and Clinical Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. (8) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. (9) Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. (10) Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. (11) Division of Rheumatology and Clinical Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. (12) Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. Parker Institute for Cancer Immunotherapy at University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. (13) Center for Systems Immunology, Departments of Immunology and Computational & Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. (14) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. (15) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. dvignali@pitt.edu. Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. dvignali@pitt.edu. Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. dvignali@pitt.edu.
