TY - JOUR
T1 - IL-7R-dependent phosphatidylinositol 3-kinase competes with the STAT5 signal to modulate t cell development and homeostasis
AU - Cui, Guangwei
AU - Shimba, Akihiro
AU - Ma, Guangyong
AU - Takahara, Kazuhiko
AU - Tani-Ichi, Shizue
AU - Zhu, Yuanbo
AU - Asahi, Takuma
AU - Abe, Akifumi
AU - Miyachi, Hitoshi
AU - Kitano, Satsuki
AU - Hara, Takahiro
AU - Yasunaga, Jun Ichirou
AU - Suwanai, Hirotsugu
AU - Yamada, Hisakata
AU - Matsuoka, Masao
AU - Ueki, Kohjiro
AU - Yoshikai, Yasunobu
AU - Ikuta, Koichi
N1 - Funding Information:
This work was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI Grants 17K15721 (to G.C.), 16H05172, and 16K15288 (to K.I.) and by the Shimizu Foundation for Immunology and Neuroscience grant for 2016 (to G.C.). It was also supported by a grant from the Takeda Science Foundation (to G.C.), a grant from the Tokyo Biochemical Research Foundation (to G.M.), the Joint Usage/ Research Center program of the Institute for Frontier Life and Medical Sciences
Publisher Copyright:
© 2020 by The American Association of Immunologists, Inc.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/2/15
Y1 - 2020/2/15
N2 - 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.
AB - 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.
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U2 - 10.4049/jimmunol.1900456
DO - 10.4049/jimmunol.1900456
M3 - Article
C2 - 31924648
AN - SCOPUS:85079022147
VL - 204
SP - 844
EP - 857
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 4
ER -