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J Immunol. 2017 Sep 15;199(6):1961-1966. doi: 10.4049/jimmunol.1700375. Epub 2017 Aug 2.

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

Author information

1
Department of Surgery, Emory University, Atlanta, GA 30322.
2
Emory Transplant Center, Emory University, Atlanta, GA 30322.
3
Emory Critical Care Center, Emory University, Atlanta, GA 30322.
4
Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322.
5
Beth Israel Deaconess Medical Center, Harvard University, Boston, MA 02215; and.
6
Division of Pulmonary, Allergy, Critical Care and Sleep, Department of Medicine, Emory University, Atlanta, GA 30322.
7
Department of Surgery, Emory University, Atlanta, GA 30322; mandy.ford@emory.edu.

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.

PMID:
28768726
PMCID:
PMC5587400
DOI:
10.4049/jimmunol.1700375
[Indexed for MEDLINE]
Free PMC Article

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