CTLA-4 Checkpoint Inhibition Improves Sepsis Survival in Alcohol-Exposed Mice.

Autor:	Paterson CW; Department of Surgery, Emory Critical Care Center, Emory University School of Medicine, Atlanta GA.; Lieutenant, Medical Corps, Naval Reserve Officer Training Corp, United States Navy, Atlanta, GA., Fay KT; Department of Surgery, Emory Critical Care Center, Emory University School of Medicine, Atlanta GA., Chen CW; Department of Surgery, Emory Critical Care Center, Emory University School of Medicine, Atlanta GA., Klingensmith NJ; Department of Surgery, Emory Critical Care Center, Emory University School of Medicine, Atlanta GA., Gutierrez MB; Department of Surgery, Emory Critical Care Center, Emory University School of Medicine, Atlanta GA., Liang Z; Department of Surgery, Emory Critical Care Center, Emory University School of Medicine, Atlanta GA., Coopersmith CM; Department of Surgery, Emory Critical Care Center, Emory University School of Medicine, Atlanta GA., Ford ML; Department of Surgery, Emory Transplant Center, Emory University School of Medicine, Atlanta GA.
Jazyk:	angličtina
Zdroj:	ImmunoHorizons [Immunohorizons] 2024 Jan 01; Vol. 8 (1), pp. 74-88.
DOI:	10.4049/immunohorizons.2300060
Abstrakt:	Chronic alcohol use increases morbidity and mortality in the setting of sepsis. Both chronic alcohol use and sepsis are characterized by immune dysregulation, including overexpression of T cell coinhibitory molecules. We sought to characterize the role of CTLA-4 during sepsis in the setting of chronic alcohol exposure using a murine model of chronic alcohol ingestion followed by cecal ligation and puncture. Results indicated that CTLA-4 expression is increased on CD4+ T cells isolated from alcohol-drinking septic mice as compared with either alcohol-drinking sham controls or water-drinking septic mice. Moreover, checkpoint inhibition of CTLA-4 improved sepsis survival in alcohol-drinking septic mice, but not water-drinking septic mice. Interrogation of the T cell compartments in these animals following pharmacologic CTLA-4 blockade, as well as following conditional Ctla4 deletion in CD4+ T cells, revealed that CTLA-4 deficiency promoted the activation and proliferation of effector regulatory T cells and the generation of conventional effector memory CD4+ T cells. These data highlight an important role for CTLA-4 in mediating mortality during sepsis in the setting of chronic alcohol exposure and may inform future approaches to develop targeted therapies for this patient population. (Copyright © 2024 The Authors.)
Databáze:	MEDLINE
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