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

Thursday, June 23, 2022

3:00 PM – 3:15 PM PT

Location: Salons 3/4

Authors: Stephanie Grebinoski, n/a (Presenting Author) - University of Pittsburgh; Qianxia Zhang, PhD (Co-Author) - Harvard University; Anthony Cillo, PhD (Co-Author) - University of Pittsburgh; Sasikanth Manne, n/a (Co-Author) - Institute for Immunology, Perelman School of Medicine, University of Pennsylvania; Hanxi Xiao, n/a (Co-Author) - University of Pittsburgh; Erin Brunazzi, n/a (Co-Author) - University of Pittsburgh; Tracy Tabib, n/a (Co-Author) - University of Pittsburgh; Carly Cardello, n/a (Co-Author) - University of Pittsburgh; Christine Lian, MD (Co-Author) - Harvard University; George Murphy, MD (Co-Author) - Harvard University; Robert Lafyatis, MD (Co-Author) - University of Pittsburgh; E. John Wherry, n/a (Co-Author) - Institute for Immunology, Perelman School of Medicine, University of Pennsylvania; Jishnu Das, PhD (Co-Author) - University of Pittsburgh; Creg J. Workman, PhD (Co-Author) - University of Pittsburgh School of Medicine; Dario AA Vignali, PhD (Co-Author) - University of Pittsburgh School of Medicine

Presenting Author(s)

Stephanie Grebinoski, BS

Graduate Student Researcher
University of Pittsburgh
PITTSBURGH, Pennsylvania, United States

Chair(s)

Irini Sereti, MD

Senior Investigator- Section Chief
National Institute of Allergy and Infectious Diseases
Bethesda, Maryland, United States

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.