PI3Kδ: a key driver of effector differentiation under conditions of T cell exhaustion
نویسندگان
چکیده
Abstract In chronic infection and cancer, prolonged antigen exposure drives a state of T cell hyporesponsiveness, called exhaustion. A small subset TCF1 +progenitor exhausted stem-like cells (pTex) cells, is required to maintain (Tex) respond checkpoint blockade. Understanding mechanisms regulating these populations may help identify approaches counter Phosphatidylinositol 3-kinase-d (PI3Kd) an important component signaling. We have found that TCF-1 repressed in CD8 +T from patients with Activated PI3K Delta Syndrome mouse model (Pik3cd E1020K/+mice) acute viral infections. How activated-PI3Kδ affects exhaustion unknown. Using LCMV clone 13 infection, we Pik3cd E1020K/+mice rapidly die, yet surviving mice recover faster than WT. RNA sequencing revealed decreased expression Tcf7, encoding TCF-1, antigen-specific along loss +Tim3 −CD8 +pTex upon cl13 infection. Tex were maintained during displayed effector-like phenotype, CX3CR1 +and KLRG1 +, increased effector functions, suggesting might induce early immunopathology increase clearance. P14 transfers, conjunction CRISPR-mediated gene disruption, FoxO1 leads +cells, whereas the at least partially cell-extrinsic. Our findings suggest PI3Kδ critical rheostat balances vs differentiation, providing insight for therapeutic strategies
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ژورنال
عنوان ژورنال: Journal of Immunology
سال: 2023
ISSN: ['1550-6606', '0022-1767']
DOI: https://doi.org/10.4049/jimmunol.210.supp.226.05