RAS P21 Protein Activator 3 finetunes Type I immunity by limiting HCK-mediated STAT4 phosphorylation

Type I immunity, mediated by IFN-γ, is essential for combating intracellular pathogens but also drives inflammatory diseases. How the immune system balances protective type I responses with pathological inflammation is elusive. While the IL-12-STAT4 pathway that promotes IFN-γ production is well-established, the intrinsic negative regulators remain unclear. We establish that RASA3 serves as a permissive checkpoint for type I immune responses. T cell-specific ablation of RASA3 amplified Th1/Tc1 immunity and IFN-γ expression, enhancing the clearance of Listeria monocytogenes but exacerbating allergic contact dermatitis. We further identify the hematopoietic cell kinase (HCK) as a direct kinase for STAT4, which binds to and phosphorylates it at the Tyr693 residue to elicit IFN-γ production. Mechanistically, RASA3 represses the translation of HCK via constraining ribosomal protein RPL36A expression. Additionally, the RASA3-HCK axis is conserved in human Th1 cells. Thus, we define a critical role of the RASA3-HCK-STAT4 axis in fine-tuning type I immunity and offer promising targets for intervening in Th1/Tc1-driven pathologies.