Examining Helper T-cell Recovery After Sepsis

Abstract

Sepsis strikes 750,000 Americans every year with ~ 210,000 of these patients dying – far more than the number of deaths from prostate cancer, breast cancer, and AIDS combined. Some of these deaths occur during the acute, inflammatory stages of sepsis, but ~70% of these patients survive the initial infection, only to perish due to hospital-acquired infections. Most sepsis research has focused on understanding the acute, inflammatory stage of sepsis, but the increased susceptibility to secondary infections has led clinicians and researchers to believe that the chronic stage of sepsis is important and is characterized by immunosuppression. CD4 T-cells, essential for coordinating immune responses to opportunistic pathogens, are severely depleted during the acute stage of sepsis, but gradually recover throughout the immunosuppressive phase of sepsis. Despite the well-characterized immune cell apoptosis during sepsis, the impact of sepsis on protective T-cell responses (especially CD4 T-cells) against secondary pathogen challenge remains poorly understood. This dissertation presents a previously unappreciated mechanism of CD4 T-cell impairment during the immunosuppressive stage of sepsis. In the present study, we have studied sepsis immunosuppression by using Class II major histocompatibility complex tetramers to track endogenous, antigen specific CD4 T-cells, in order to examine a hypothesis: that the uneven recovery of the Ag-specific CD4 T-cell repertoire contributes to the alarming rate of infections in sepsis survivors. In addition, we have examined the impact of enteric microbial populations in the recovery of CD4 T-cells after sepsis. The results described present a previously unappreciated mechanism of CD4 T-cell impairment during the immunosuppressive stage of sepsis.