Anti-TIGIT differentially affects sepsis survival in immunologically experienced versus previously naive hosts

• Type of Material: Article
• Authors: Yini Sun, Emory University; Jerome C. Anyalebechi, Emory University; He Sun, Emory University; Tetsuya Yumoto, Emory University; Ming Xue, Emory University; Danya Liu, Emory University; Zhe Liang, Emory University; Craig Coopersmith, Emory University; Mandy Ford, Emory University
• Language: English
• Date: 2021-03-08
• Publisher: AMER SOC CLINICAL INVESTIGATION INC
• Publication Version: Final Published Version
• Copyright Statement: © 2021 Sun et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1172/jci.insight.141245
• Title of Journal or Parent Work: JCI INSIGHT
• Volume: 6
• Issue: 5
• Grant/Funding Information: This work was funded by NIH R01 grants AI149724, GM113228, GM104323, and GM072808 (to MLF and CMC).
• Keywords: Life Sciences & Biomedicine; Science & Technology; Medicine, Research & Experimental; IMMUNOSUPPRESSION; STRATEGIES; REGULATORY T-CELLS; RECEPTORS; Research & Experimental Medicine; MORTALITY
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Immunology; Biology, Cell

Abstract

Mounting evidence suggests that the balance of T cell costimulatory and coinhibitory signals contributes to mortality during sepsis. Here, we identified a critical role of the coinhibitory molecule T cell Ig and ITIM domain (TIGIT) in regulating sepsis mortality. Because TIGIT is significantly upregulated on memory T cells, we developed a “memory mouse” model to study the role of TIGIT during sepsis in a more physiologically relevant context. Mice received sequential pathogen exposure and developed memory T cell frequencies, similar to those observed in adult humans, and were then subjected to sepsis induction via cecal ligation and puncture. Our results show that targeting the TIGIT pathway during sepsis is fundamentally different in previously naive versus memory mice, in that αTIGIT Ab had no effect on survival in previously naive septic mice but sharply worsened survival in memory septic mice. Mechanistically, αTIGIT increased apoptosis of memory T cells, decreased T cell function, and downregulated the costimulatory receptor DNAM on memory CD8+ T cells in memory septic mice, but not in previously naive septic mice. Additionally, αTIGIT diminished Helios expression in Tregs in memory but not previously naive septic mice. These data highlight fundamental differences in the pathophysiological impact of targeting TIGIT in immunologically experienced versus previously naive hosts during sepsis.