Sunday, May 5, 2024
5/5/2024
Sepsis is life-threatening organ dysfunction caused by a dysregulated host response to infection. The immune system plays a central role in this dysregulated host response; immune abnormalities have been identified in clinical sepsis and in murine cecal ligation and puncture (CLP), the most widely-used animal model of sepsis. However, the effect of a significant aspect of the immune response, the memory T cell response, has escaped investigation in the CLP model. Recent studies have demonstrated that laboratory mice lack a well-developed repertoire of memory T cells, a deficiency not present in mice “in the wild” – or in patients with sepsis. Thus, the contribution of this vital component of adaptive immunity is unknown. This gap in our understanding of the role of memory T cell populations in CLP assumes even greater importance considering reports that immune responses to sub-lethal infections in laboratory mice and “wild” mice differed substantially. Therefore, we undertook preliminary studies to determine if lack of this memory T cell component substantially effects responses to CLP. To induce a robust memory T cell repertoire, we treated C57Bl6 mice with an activating antibody to CD3e, activating a diverse repertoire of T cells and inducing both CD4 and CD8 T cell memory while decreasing naïve T cell proportions without altering total T cell numbers. These “immune educated” mice (following a 35 day rest) respond quite differently to CLP when challenged, with an increased numbers of IFN¿- producing CD4 T cells and a decreased numbers of TNFa producing CD8 T cells. Other changes seen in educated mice included increased neutrophil infiltration into the liver and enhancement of monocyte function. Importantly, CLP in educated mice was also associated with altered liver function, bacterial clearance, and weight loss. These findings lead to our global hypothesis: immune education alters the effects of CLP on organ function, innate immunity and outcomes. We will test this hypothesis via through comparison of immune educated mice treated with the anti-CD3e antibody to naïve mice following CLP. We will initially identify variation in physiologic presentation and parameters of organ dysfunction and clinical outcomes along with differences in the immune response to CLP in both the innate and adaptive immune response. Once we have identified specific variations, we will determine causative T cell populations through specific T cell knockouts along with adoptive transfer experiments of memory and naïve T cells. Furthermore, we will collect peripheral blood samples from septic patients and healthy control patients and examine memory T cell populations and innate immune cell function in sepsis. Ultimately, these experiments will demonstrate the role of memory T cells in CLP and the septic immune response. Moreover, determination of this role may offer potential novel therapies for sepsis and perhaps other severe infectious or inflammatory disorders.
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