TGF-beta regulates the stem-like state of PD-1(+) TCF-1(+) virus-specific CD8 T cells during chronic infection

• Type of Material: Article
• Authors: Yinghong Hu, Emory University; William Hudson, Emory University; Haydn Kissick, Emory University; Chrsitopher B Medina, Emory University; Antonio P Baptista, Ghent University; Chaoyu Ma, University of Texas Health Science Center at San Antonio; Wei Liao, University of Texas Health Science Center at San Antonio; Ronald N Germain, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda; Shannon J Turley, Genentech Inc; Rafi Ahmed, Emory University
• Language: English
• Date: 2022-08-18
• Publisher: ROCKEFELLER UNIV PRESS
• Publication Version: Final Published Version
• Copyright Statement: © 2022 Hu et al.
• License: Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1084/jem.20211574
• Title of Journal or Parent Work: JOURNAL OF EXPERIMENTAL MEDICINE
• Volume: 219
• Issue: 10
• Keywords: EXHAUSTION; GROWTH-FACTOR-BETA; MAINTENANCE; EXPRESSION; Medicine, Research & Experimental; Research & Experimental Medicine; MEMORY; Science & Technology; RESPONSES; PERSISTENCE; Life Sciences & Biomedicine; RESIDENT; Immunology; IMMUNE EVASION; BLOCKADE
• Research Categories: Health Sciences, Oncology

Abstract

Recent studies have defined a novel population of PD-1+ TCF-1+ stem-like CD8 T cells in chronic infections and cancer. These quiescent cells reside in lymphoid tissues, are critical for maintaining the CD8 T cell response under conditions of persistent antigen, and provide the proliferative burst after PD-1 blockade. Here we examined the role of TGF-β in regulating the differentiation of virus-specific CD8 T cells during chronic LCMV infection of mice. We found that TGF-β signaling was not essential for the generation of the stem-like CD8 T cells but was critical for maintaining the stem-like state and quiescence of these cells. TGF-β regulated the unique transcriptional program of the stem-like subset, including upregulation of inhibitory receptors specifically expressed on these cells. TGF-β also promoted the terminal differentiation of exhausted CD8 T cells by suppressing the effector-associated program. Together, the absence of TGF-β signaling resulted in significantly increased accumulation of effector-like CD8 T cells. These findings have implications for immunotherapies in general and especially for T cell therapy against chronic infections and cancer.