An alternative NFAT-activation pathway mediated by IL-7 is critical for early thymocyte development

Interleukin 7 (IL-7) signaling is essential during early lymphocyte development. Patra and colleagues identify a distinct IL-7–kinase Jak3–dependent pathway that activates the transcription factor NFATc1 in DN1 thymocytes to promote their survival. Interleukin 7 (IL-7) has a critical role in the development of early CD4 − CD8 − double-negative (DN) thymocytes. Although the transcription factor STAT5 is an important component of IL-7 signaling, differences in the phenotypes of mice deficient in STAT5, IL-7, IL-7 receptor alpha (IL-7rα) or the kinase Jak3 suggest the existence of STAT5-independent IL-7 signaling. Here we found that IL-7–Jak3 signals activated the transcription factor NFATc1 in DN thymocytes by phosphorylating Tyr371 in the regulatory region of NFATc1. This NFAT-activation pathway was critical for the survival and development of DN thymocytes, as deficiency in NFATc1 blocked thymocyte development at the DN1 stage, leading to T cell lymphopenia. In addition, our results demonstrated a cooperative function for NFATc1 and STAT5 in guiding thymocyte development in response to IL-7 signals.