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

• DOI: 10.1038/ni.2507
• Publication Date: 2012-12-21T16:03:29Z
• Authors: Amiya K Patra; Andris Avots; René P Zahedi; Thomas Schüler; Albert Sickmann; Ursula Bommhardt; Edgar Serfling
• Keywords: Receptors, Interleukin-7; Thymocytes; NFATC Transcription Factors; Transcription, Genetic; CD8 Antigens; Interleukin-7; Janus Kinase 3; Cell Differentiation; Mice, Transgenic; Mice; 03 medical and health sciences; 0302 clinical medicine; Gene Expression Regulation; Lymphopenia; CD4 Antigens; STAT5 Transcription Factor; Animals; Phosphorylation; Promoter Regions, Genetic; Signal Transduction

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.