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Sepsis erodes CD8 + memory T cell‐protective immunity against an EBV homolog in a 2B4‐dependent manner
Author(s) -
Xie Jianfeng,
Crepeau Rebecca L.,
Chen Chingwen,
Zhang Wenxiao,
Otani Shunsuke,
Coopersmith Craig M.,
Ford Mandy L.
Publication year - 2019
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1002/jlb.4a0718-292r
Subject(s) - sepsis , cd8 , immunology , biology , t cell , immune system , cytotoxic t cell , adoptive cell transfer , immunity , viral load , virus , virology , microbiology and biotechnology , biochemistry , in vitro
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 with 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, whereas 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.