Project Details

Early Career

Status: Funded - Open

Contributions of Memory CD4 and CD8 T Cells to Sepsis Induced Immune and Organ Dysfunction

Matthew Taylor, MD

Summary

BACKGROUND: Laboratory mice housed in pathogen free facilities and “wild” animals from less restricted environments responded to inflammatory insults in markedly different ways, and one of the primary differences is a significant repertoire of memory T cells (with a concomitant decrease in naïve T cells). The effect of the generation of a large, diverse T cell memory population on sepsis, a population which is seen in adult humans, has not been examined and may contribute to the wide variability in sepsis susceptibility, presentation and response to treatments seen in human sepsis.

GAP: Sepsis, defined as life-threatening organ dysfunction caused by a dysregulated host response to infection, is a major source of mortality and morbidity in children worldwide and remains poorly understood without specific therapies. The experiments outlined here will establish the contribution of a large, diverse population of memory T cells on immune dysregulation and organ dysfunction in cecal ligation and puncture (CLP), a widely accepted mouse model of sepsis.

HYPOTHESIS: CLP in immune educated mice will induce altered host response and organ dysfunction that differs from that following CLP in immune naïve mice.

METHODS: We will educate mice using a novel non-specific T cell memory induction through injection of wild type (WT) C57Bl/6 mice (Jackson Laboratories) with 50ug anti-CD3 activating antibody clone 145-2C11 (Biolegend), a process termed “education.” Following education, mice will undergo cecal ligation and puncture and we will characterize changes in immune function, organ dysfunction and survival.

RESULTS: Pending

IMPACT: If these studies demonstrate that CLP-induced organ dysfunction and immune dysregulation can be altered by enhancing the memory T cell repertoire, we will determine if more targeted manipulation of memory T cells, via immunization, activating drugs or administration of specific populations of memory T cells themselves (approaches currently used to treat cancer and autoimmunity) alter responses to CLP; these experiments would set the stage for trials in human sepsis.