IL17F+ naïve and IFNγ+ memory CD8 T cells drive hepatic dysfunction in the cecal ligation and puncture model of sepsis.

T cell memory significantly alters the immune response and organ dysfunction induced by the murine cecal ligation and puncture (CLP) model of sepsis. Enhanced T cell memory activation promotes hepatic neutrophilic responses and induces hepatic dysfunction, which is a common complication of human sepsis associated with poor outcomes. We used a novel Immune Educated CLP sepsis mouse model to examine the role of memory T cell cytokine responses in driving innate immunity and organ dysfunction. Through this approach, we found that induced T cell memory prior to CLP led to higher serum levels of IL12, TNF, IL17, and IL1β – all dependent on memory CD8 T cell derived IFNγ following CLP. IFNγ induced activated hepatic IL12+ monocyte-derived dendritic cells. Increased neutrophilic responses occurred in Educated CLP which was found to depend on TNF, and were suppressed by IFNγ. Hepatic dysfunction in response to CLP was worsened by CD4 and CD8 T cell immune memory and prevented by IFNγ and IL17F blockade. These findings were recapitulated in naturalized outbred pet shop mice with natural immune memory to provide translational relevance to our Immune Educated CLP sepsis model. IL17F or IFNγ blockade may represent potential targets for treatment in sepsis with hepatic dysfunction.