Cutting Edge: 2B4-Mediated Coinhibition of CD4(+) T Cells Underlies Mortality in Experimental Sepsis

• Type of Material: Article
• Authors: Ching-Wen Chen, Emory University; Rohit Mittal, Emory University; Nathan J. Klingensmith, Emory University; Eileen Burd, Emory University; Cox Terhorst, Harvard University; Greg Martin, Emory University; Craig Coopersmith, Emory University; Mandy L Ford, Emory University
• Language: English
• Date: 2017-09-15
• Publisher: American Association of Immunologists
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 by The American Association of Immunologists, Inc.
• Final Published Version (URL): http://dx.doi.org/10.4049/jimmunol.1700375
• Title of Journal or Parent Work: Journal of Immunology
• ISSN: 0022-1767
• Volume: 199
• Issue: 6
• Start Page: 1961
• End Page: 1966
• Grant/Funding Information: This work was supported by R01GM113228 (M.L.F. and C.M.C), R01AI104699 (M.L.F.) T32GM095442 (C.M.C), R01GM072808 (C.M.C), R01GM104323 (C.M.C., M.L.F.), R01GM109779 (C.M.C., M.L.F.).
• Keywords: Life Sciences & Biomedicine; DYSFUNCTION; Science & Technology; Immunology; EXPRESSION
• Research Categories: Health Sciences, Immunology

Abstract

Sepsis is a leading cause of death in the United States, but the mechanisms underlying sepsis-induced immune dysregulation remain poorly understood. 2B4 (CD244, SLAM4) is a cosignaling molecule expressed predominantly on NK cells and memory CD8+ T cells that has been shown to regulate T cell function in models of viral infection and autoimmunity. In this article, we show that 2B4 signaling mediates sepsis lymphocyte dysfunction and mortality. 2B4 expression is increased on CD4+ T cells in septic animals and human patients at early time points. Importantly, genetic loss or pharmacologic inhibition of 2B4 significantly increased survival in a murine cecal ligation and puncture model. Further, CD4-specific conditional knockouts showed that 2B4 functions on CD4+ T cell populations in a cell-intrinsic manner and modulates adaptive and innate immune responses during sepsis. Our results illuminate a novel role for 2B4 coinhibitory signaling on CD4+ T cells in mediating immune dysregulation.