Investigating the DNA damage and repair mechanisms of Th1 cells in febrile temperature 3774

Abstract Description Inflammation is a natural response that the body uses to fight against injuries and infections. Distinct CD4+ T cell subsets play crucial roles in mediating the inflammatory responses, with Th1 and Th17 cells producing pro-inflammatory cytokines. One hallmark feature of inflammation is heat generation, and a recent study reveals the fate of distinct CD4+ T-cell subsets in the febrile environment. While both Th1 and Th17 cells exhibit elevated cytokine production when exposed to a higher temperature, Th1 cells are more vulnerable to mitochondrial dysfunction. Th1 cells suffer from higher mitochondria reactive oxygen species (ROS) production and ROS-dependent DNA damage. Interestingly, Th1 cells exhibit increased cytosolic mtDNA, which induces the activation of the cGAS-STING pathway. Despite the understanding of temperature-induced DNA damage in Th1 cells, it remains unclear whether mtDNA damage is the major driver of mitochondrial dysfunction. My project aims to identify the mtDNA damage response in Th1 cells under heat stress and investigate whether impaired mtDNA protection and repair mechanisms disrupt mitochondrial integrity. In addition, my research also aims to examine the mechanism mediating the mtDNA leakage and whether the activation of the innate immune pathway is due to insufficient cytosolic DNA removal and degradation. Ultimately, my project provides insights into the cellular immune response in many chronic inflammatory diseases, including rheumatoid arthritis. Funding Sources NIH: DK105550-11 and NIH: RCA217987-05 Topic Categories Cellular Adhesion, Migration, and Inflammation (CAM)