Sepsis erodes CD8+ memory T cell-protective immunity against an EBV homolog in a 2B4-dependent manner

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 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.

CD4 T Cell Responses and the Sepsis-Induced Immunoparalysis State

“…The memory CD8 T cells that remain following sepsis display defects in Ag-dependent and -independent functions including reduced Ag-sensitivity, proliferative capacity, and ability to produce cytokines in a bystander manner (41). Furthermore, memory CD8 T cells from hosts that have recovered from sepsis are more prone to undergo exhaustion when combating chronic infections, displaying increased expression of inhibitory receptors PD-1 and 2B4, reduced ability to produce effector cytokines IFN-γ and TNF-α, and reduced ability to clear the infection (42)(43)(44). Interestingly, numerical loss and functional defects are not as profound for infection-induced tissue resident memory (T RM ) CD8 T cells in hosts that survive sepsis.…”

IL-17, IL-27, and IL-33: A Novel Axis Linked to Immunological Dysfunction During Sepsis

“…In addition to the induction of this cell population, IL-27 signaling leads to an increase in co-inhibitory molecule expression on T cells following chronic antigen exposure and during cancer (75). As T cell dysfunction and exhaustion is associated with the development of immunosuppression during sepsis and ultimately worsened survival (76–79), IL-27 could be an effective therapeutic target. However, mice can produce IL-27p28 in the absence of EBI3, so it is unclear if the reported effects of IL-27 during sepsis are actually due to the full heterodimeric cytokine or merely to its alpha subunit.…”

Immune Cell Number, Phenotype, and Function in the Elderly with Sepsis

“…Antigen-specific memory CD8 + T cells are responsible for immunosurveillance that protects against pathogens that are re-encountered and the reactivation of latent viral infections [ 165 ]. However, sepsis reduces the protective effects of these cells by decreasing their number and function [ 161 ]; therefore, the impact of sepsis on CD8 + T cells increases susceptibility to secondary infection and mortality.…”