Wednesday, April 2, 2025
4/2/2025
Investigating mechanisms of bystander CD8 T cell mediated immunopathology - Project Abstract Defining mechanisms of CD8+ T cell immune dysfunction is critical to treating immune-mediated diseases. Bystander memory CD8+ T cells, in particular, are known to be protective to the host by supporting pathogen clearance and infection control early in an infection by producing and responding to pro-inflammatory cytokines and direct killing of infected cells. However, in some human disease contexts, dysregulation of bystander memory CD8+ T cells has led to immunopathology and poor disease outcomes. The factors that drive this phenomenon are unclear. We developed a mouse model to explore the pathological contexts and consequences of bystander memory CD8+ T cells. In our model, immunity to lymphocytic choriomeningitis virus (LCMV) leads to impaired control of an infection with the unrelated bacteria, Listeria monocytogenes (Lm). Our preliminary data indicate that mice carrying increased frequencies of LCMV-specific memory CD8+ T cells (P14 TCR transgenic cells) die following wild type (WT) Lm. Additionally, our preliminary data suggest that exaggerated inflammation is not the cause of this pathology, as LCMV-immune mice did not have improved bacterial clearance compared to naïve controls and they had markedly elevated levels of serum IL- 10, an anti-inflammatory cytokine. We hypothesize that elevated IL-10 and LCMV-specific bystander memory CD8+ T cell sensitivity to IL-10 is central to dysregulated Lm control in our model. Following this, abundant bystander memory CD8+ T cells cause fatal tissue damage by inappropriate cytolysis of uninfected cells, via innate-like mechanisms. I propose the following aims to test these hypotheses: Aim 1 will identify the function of IL-10 during a bystander Lm infection of LCMV-immune mice, by IL-10RA blockade and by ablating IL-10R on bystander memory CD8+ T cells. Aim 2 will determine the basis for bystander memory CD8+ T cell induced lethal immunopathology by modulating P14 TCR CD8+ T cells to ablate genes encoding key proteins involved in bystander immune responses. Together this proposal addresses an important knowledge gap into mechanisms of immune dysfunction induced by bystander memory CD8+ T cells.
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