Sustained and incomplete recovery of naive CD8⁺ T cell precursors after sepsis contributes to impaired CD8⁺ T cell responses to infection

Patients who survive severe sepsis often display compromised immune function with impairment in innate and adaptive immune responses. These septic patients are highly susceptible to "secondary" infections with intracellular pathogens that are usually controlled by CD8⁺ T cells. It is not known when and if this observed immunoparalysis of CD8⁺ T cell immunity recovers, and the long-term consequences of sepsis on the ability of naive CD8⁺ T cells to respond to subsequent infections are poorly understood. In this study, using the cecal-ligation and puncture mouse model of sepsis, we show that sepsis induces a rapid loss of naive CD8⁺ T cells. However, IL-15-dependent numerical recovery is observed a month after initial septic insult. Numerical recovery is accompanied by IL-15-dependent phenotypic changes where a substantial proportion of naive (Ag-inexperienced) CD8⁺ T cells display a "memory-like" phenotype (CD44 ^hi/CD11a^hi). Importantly, the impairment of naive CD8 ⁺ T cells to respond to viral and bacterial infection was sustained for month(s) after sepsis induction. Incomplete recovery of naive CD8 ⁺ T cell precursors was observed in septic mice, suggesting that the availability of naive precursors contributes to the sustained impairment in primary CD8⁺ T cell responses. Thus, sepsis can result in substantial and long-lasting changes in the available CD8⁺ T cell repertoire affecting the capacity of the host to respond to new infections.