Differential lymphopenia-induced homeostatic proliferation for CD4+ and CD8+ T cells following septic injury

Abstract

Sepsis is a severe, life‐threatening infection and a leading cause of death in hospitals. A hallmark of sepsis is the profound apoptosis‐induced depletion of lymphocytes generating a lymphopenic environment. As lymphopenia can induce nonantigen‐driven homeostatic proliferation (HP), we examined this process during sepsis. CD4⁺ and CD8⁺ T cells, which were depleted within 24 h of sepsis induction, remained at significantly reduced levels until Day 21 when normal numbers were detected. When HP was examined, naïve CD8⁺ T cells proliferated between Day 7 and Day 21 post‐cecal ligation and puncture, developing into memory cells with relatively few cells expressing an activation phenotype. Conversely, naïve CD4⁺ T cells did not undergo HP, but proportionally higher numbers expressed activation markers. Adoptive transfer studies revealed that T cells from mice that had recovered from sepsis were not protective when transferred to naïve mice undergoing sepsis. In addition, the TCR repertoire was not skewed toward any specific Vβ type but resembled the repertoire found in normal mice, suggesting that T cells were not primed to antigens resulting from the infection. Interestingly, depletion of endogenous CD8⁺ but not CD4⁺ T cells restored the ability of naive CD4⁺ T cells to undergo HP, increasing the number of CD4⁺ T cells with memory but not activation markers. We conclude that homeostatic control in the postseptic environment permits recovery of the T cell repertoire to normal levels without generating antigen‐specific memory or aberrant T cell specificities. Restoration of homeostatic control mechanisms might be a rational therapy for this disorder.