IL-7R-dependent phosphatidylinositol 3-kinase competes with the STAT5 signal to modulate t cell development and homeostasis

T cell development and homeostasis requires IL-7R a-chain (IL-7Ra) signaling. Tyrosine Y449 of the IL-7Ra is essential to activate STAT5 and PI3K, whereas PI3K recruitment requires IL-7Ra methionine M452. How IL-7Ra activates and regulates both signaling pathways differentially remains unclear. To characterize differential signaling, we established two lines of IL-7Ra mutant mice: IL-7R-Y449F mice and IL-7R-M452L mice. IL-7R-Y449F mice showed decreased PI3K and STAT5 signals, whereas IL-7R-M452L mice showed decreased PI3K but significantly increased STAT5 signaling, owing to a competition between PI3K and STAT5 signaling through Y449 of IL-7Ra. The number of T, B, and mature innate lymphoid cells were markedly reduced in IL-7R-Y449F mice, whereas IL-7R-M452L mice showed impaired early T cell development and memory precursor effector T cell maintenance with the downregulation of transcription factor T cell factor-1. Peripheral T cell numbers increased in IL-7R-M452L mice with enhanced survival and homeostatic proliferation. Furthermore, although wild type and IL-7R-Y449F mice showed comparable Th1/Th2 differentiation, IL-7R-M452L mice exhibited impaired Th17 differentiation. We conclude that PI3K competes with STAT5 under IL-7Ra and maintains an appropriate signal balance for modulating T cell development and homeostasis. To our knowledge, this study provides a new insight into complex regulation of IL-7Ra signaling, which supports immune development and responses.