Determining the role of early activated CD4+ T cells in effector differentiation 4596

Abstract Description Metabolic reprogramming is known to shape CD4+ T cell response to antigen and subsequent differentiation, but the precise metabolic requirements for adopting an effector phenotype and the molecular mechanisms controlling this remain incompletely understood. Upon antigen recognition, CD4+ T cells shift from oxidative phosphorylation (OXPHOS) to aerobic glycolysis. We recently examined CD4+ T cell responses to the type I pathogen Listeria monocytogenes and identified a transient population with simultaneously high glycolysis and OXPHOS. These early activated (EA) cells differentiated into Th1 cells upon adoptive transfer, suggesting that Th1 cells transit through an EA state during effector differentiation. High OXPHOS, driven by electron transport chain (ETC) complexes I and III, generates reactive oxygen species (ROS), an important signaling molecule that modulates transcription factors such as AP-1. EA cells exhibited elevated ROS levels, potentially due to high levels of OXPHOS, and treatment of EA cells with ROS scavengers reduced proliferation and IFNγ production. Inhibiting ETC I or III, but not II or V also decreased mitochondrial ROS, proliferation, and IFNγ production. Furthermore, we identified AP-1 as a key regulator in EA cells, with high binding at effector and proliferation genes and increased cFOS and cJUN activation. These findings suggest transiently high OXPHOS and ROS production are critical for AP-1 activation, T cell proliferation, and effector function. Funding Sources HHMI Gilliam Fellowship, AACR NextGen Transformative Cancer Research Award and the Parker Institute for Cancer Immunotherapy, Cancer Reserach Institute STAR Grant Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)