Chronic Alcohol Ingestion Delays T Cell Activation and Effector Function in Sepsis

• Type of Material: Article
• Authors: Lindsay M. Margoles, Emory University; Rohit Mittal, Emory University; Nathan J. Klingensmith, Emory University; John D. Lyons, Emory University; Zhe Liang, Emory University; Mara A. Serbanescu, Emory University; Maylene E. Wagener, Emory University; Craig Coopersmith, Emory University; Mandy Ford, Emory University
• Language: English
• Date: 2016-11-18
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: © 2016 Margoles et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.pone.0165886
• Title of Journal or Parent Work: PLoS ONE
• ISSN: 1932-6203
• Volume: 11
• Issue: 11
• Start Page: e0165886
• End Page: e0165886
• Grant/Funding Information: National Institute of General Medical Sciences R01GM109779 to Mandy L. Ford. National Institutes of Health GM113228 to Craig M. Coopersmith. NIGMS GM095442 to Craig M. Coopersmith.; National Institute on Alcohol Abuse and Alcoholism P50AA013757 to Craig M. Coopersmith.; This work was supported by National Institutes of Health (NIGMS R01GM109779, R01GM109779, and R01 GM113228 jointly to MLF and CMC, and T32GM095442 to CMC and the NIH/Emory Lung and Alcohol Biology Center Grant P50AA013757).; This work was supported by National Institutes of Health (NIGMS R01GM109779 and R01 GM113228 to CMC and MLF and T32GM095442 to CMC and the NIH/Emory Lung and Alcohol Biology Center Grant P50AA013757).
• Keywords: DYSFUNCTION; Multidisciplinary Sciences; IMMUNE-SYSTEM; MORTALITY; CHRONIC ETHANOL-CONSUMPTION; Science & Technology - Other Topics; DIFFERENTIATION; IMMUNOTHERAPY; RESPONSES; CD69; Science & Technology; CD43; HOST-DEFENSE
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Toxicology; Health Sciences, General

Abstract

Sepsis is the leading cause of death in intensive care units in the US, and it is known that chronic alcohol use is associated with higher incidence of sepsis, longer ICU stays, and higher mortality from sepsis. Both sepsis and chronic alcohol use are associated with immune deficits such as decreased lymphocyte numbers, impaired innate immunity, delayed-type hypersensitivity reactions, and susceptibility to infections; however, understanding of specific pathways of interaction or synergy between these two states of immune dysregulation is lacking. This study therefore sought to elucidate mechanisms underlying the immune dysregulation observed during sepsis in the setting of chronic alcohol exposure. Using a murine model of chronic ethanol ingestion followed by sepsis induction via cecal ligation and puncture, we determined that while CD4+ and CD8+ T cells isolated from alcohol fed mice eventually expressed the same cellular activation markers (CD44, CD69, and CD43) and effector molecules (IFN-ã, TNF) as their water fed counterparts, there was an overall delay in the acquisition of these phenotypes. This early lag in T cell activation was associated with significantly reduced IL-2 production at a later timepoint in both the CD4+ and CD8+ T cell compartments in alcohol sepsis, as well as with a reduced accumulation of CD8dim activated effectors. Taken together, these data suggest that delayed T cell activation may result in qualitative differences in the immune response to sepsis in the setting of chronic alcohol ingestion.