Sepsis Erodes CD8+ Memory T Cell Protective Immunity Against an EBV Homolog in a 2B4-Dependent Manner

• Type of Material: Article
• Authors: J. Xie, Emory University; R. L. Crepeau, Emory University; C. W. Chen, Emory University; W. Zhang, Emory University; S. Otani, Emory University; Craig Coopersmith, Emory University; M. L. Ford, Emory University
• Language: English
• Date: 2019-03-01
• Publisher: Wiley
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2019 Society for Leukocyte Biology.
• Final Published Version (URL): http://dx.doi.org/10.1002/JLB.4A0718-292R
• Title of Journal or Parent Work: Journal of Leukocyte Biology
• Volume: 105
• Issue: 3
• Start Page: 565
• End Page: 575
• Keywords: immune memory; Immunology; Protective immunity; sepsis; CD8+ T Cell; EBV homolog; virus-specific T cell responses; Critical care
• Research Categories: Biology, Cell; Health Sciences, Immunology; Health Sciences, Medicine and Surgery

Abstract

Epstein–Barr virus (EBV) reactivation commonly occurs following sepsis but the mechanisms underlying this are unknown. We utilized a murine EBV homolog (gHV) and the cecal ligation and puncture model of polymicrobial sepsis to study the impact of sepsis on gHV reactivation and CD8+ T cell immune surveillance following a septic insult. We observed a significant increase in the frequency of gHV-infected germinal center B cells on day 7 following sepsis. This increase in viral load was associated with a concomitant significant decrease in the frequencies of gHV-specific CD8+ T cells, as measured by class I MHC tetramers corresponding to the immunodominant viral epitopes. Phenotypic analysis revealed an increased frequency of gHV-specific CD8+ T cells expressing the 2B4 coinhibitory receptor in septic animals compared to sham controls. We sought to interrogate the role of 2B4 in modulating the gHV-specific CD8+ T cell response during sepsis. Results indicated that in the absence of 2B4, gHV-specific CD8+ T cell populations were maintained during sepsis, and gHV viral load was unchanged in 2B4−/− septic animals relative to 2B4−/− sham controls. WT CD8+ T cells upregulated PD-1 during sepsis, while 2B4−/− CD8+ T cells did not. Finally, adoptive transfer studies revealed a T cell intrinsic effect of 2B4 coinhibition on virus-specific CD8+ T cells and gHV viral load during sepsis. These data demonstrate that sepsis-induced immune dysregulation erodes antigen-specific CD8+ responses against a latent viral infection, and suggest that blockade of 2B4 may better maintain protective immunity against EBV in the context of sepsis. (C) 2019 Society for Leukocyte Biology