Friday, May 9, 2025
5/9/2025
Effect of Th2-type microenvironment on CD8 TRM-mediated protection from infection - Project Summary Abstract Individuals suffering from atopic dermatitis have increased risk for serious recurrent and disseminated viral infections, but the cause is unclear. Defense against local infections relies on tissue resident memory CD8+ T cells (TRM) that deliver rapid defense against invading pathogens. We hypothesize that impairment of CD8+ TRM contributes to severe infection in patients with atopic dermatitis. Our preliminary data demonstrate that IL-4 counters TGF-b-induced expression of CD8+ TRM receptors that are required for persistence within peripheral tissues. In parallel, in vivo studies reveal that exposure of CD8+ T cells to IL-4 decreases their accumulation within inflamed skin. Based on these preliminary data, we hypothesize that IL-4 prevents TGF-b-mediated signaling and/or changes the chromatin landscape surrounding TGF-b target genes in CD8+ T cells, resulting in an altered CD8+ T cell phenotype. We predict that these phenotypic changes impede the long-term persistence of cutaneous CD8+ TRM and impair TRM-mediated defense against local viral infection. We will test these hypotheses by i) using mouse models of allergic eczema to analyze the impact of local Th2-type inflammation on CD8+ TRM persistence and protection from HSV infection ii) analyzing the effect of Th2 cytokines on the phenotype and function of human CD8+ TRM, and iii) investigating the impact of IL-4 on TGF- bR signaling and the chromatin landscape of CD8+ T cells.
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