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IL-7R-Dependent Phosphatidylinositol 3-Kinase Competes with the STAT5 Signal to Modulate T Cell Development and Homeostasis.
- Source :
-
Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2020 Feb 15; Vol. 204 (4), pp. 844-857. Date of Electronic Publication: 2020 Jan 10. - Publication Year :
- 2020
-
Abstract
- T cell development and homeostasis requires IL-7R α-chain (IL-7Rα) signaling. Tyrosine Y449 of the IL-7Rα is essential to activate STAT5 and PI3K, whereas PI3K recruitment requires IL-7Rα methionine M452. How IL-7Rα activates and regulates both signaling pathways differentially remains unclear. To characterize differential signaling, we established two lines of IL-7Rα 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-7Rα. 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-7Rα 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-7Rα signaling, which supports immune development and responses.<br /> (Copyright © 2020 by The American Association of Immunologists, Inc.)
- Subjects :
- Animals
Cell Differentiation immunology
Immunity, Innate
Mice
Mice, Inbred C57BL
Mice, Mutant Strains
Phosphatidylinositol 3-Kinases metabolism
Receptors, Interleukin-7 metabolism
STAT5 Transcription Factor metabolism
Signal Transduction immunology
Homeostasis immunology
Phosphatidylinositol 3-Kinases immunology
Receptors, Interleukin-7 immunology
STAT5 Transcription Factor immunology
T-Lymphocytes immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1550-6606
- Volume :
- 204
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Journal of immunology (Baltimore, Md. : 1950)
- Publication Type :
- Academic Journal
- Accession number :
- 31924648
- Full Text :
- https://doi.org/10.4049/jimmunol.1900456