Sepsis erodes CD8+ memory Tcell-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+ Tcell 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+ Tcells, as measured by class I MHC tetramers corresponding to the immunodominant viral epitopes. Phenotypic analysis revealed an increased frequency of gHV-specific CD8+ Tcells 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+ Tcell response during sepsis. Results indicated that in the absence of 2B4, gHV-specific CD8+ Tcell populations were maintained during sepsis, and gHV viral load was unchanged in 2B4-/- septic animals relative to 2B4-/- sham controls. WT CD8+ Tcells upregulated PD-1 during sepsis, whereas 2B4-/- CD8+ Tcells did not. Finally, adoptive transfer studies revealed a Tcell-intrinsic effect of 2B4 coinhibition on virus-specific CD8+ Tcells 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.