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The Cytokine Receptor IL-7Ra Impairs IL-2 Receptor Signaling and Constrains the In Vitro Differentiation of Foxp3+ Treg Cells

  1. Author:
    Waickman, Adam T
    Keller, Hilary R
    Kim, Tae-Hyoun
    Luckey, Megan A
    Tai, Xuguang
    Hong, Changwan
    Molina-París, Carmen
    Walsh,Scott
    Park, Jung-Hyun

  2. Author Address

    Experimental Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, NIH, Bethesda, MD 20892, USA., Experimental Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, NIH, Bethesda, MD 20892, USA; Department of Surgery, Guthrie Robert Packer Hospital, Sayre, PA, USA., Department of Anatomy, Pusan National University School of Medicine, Yangsan 50612, South Korea., Department of Applied Mathematics, School of Mathematics, University of Leeds, Leeds, UK., Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, NIH, Frederick, MD 21702, USA., Experimental Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, NIH, Bethesda, MD 20892, USA. Electronic address: parkhy@mail.nih.gov.,
    1. Year: 2020
    2. Date: AUG 21
    3. Epub Date: 2020 07 29
  2. Journal: iScience
    1. 23
    2. 8
    3. Pages: 101421
  4. Type of Article: Article
  5. Article Number: 101421
  6. ISSN: 2589-0042
  1. Abstract:

    IL-7 receptor signaling is essential for the generation and maintenance of conventional T cells. Immunosuppressive Foxp3+ Treg cells, however, express uniquely low amounts of the IL-7-proprietary IL-7Ra so that they are impaired in IL-7 signaling. Because Treg cells depend on IL-2, the loss of IL-7Ra has been considered irrelevant for Treg cells. In contrast, here, we report that IL-7Ra downregulation is necessary to maximize IL-2R signaling. Although IL-7Ra overexpression promoted IL-7 signaling, unexpectedly, IL-2 signaling was suppressed in the same cells. Mechanistically, we found that ?c, which is a receptor subunit shared by IL-7R and IL-2R, directly binds and pre-associates with IL-7Ra, thus limiting its availability for IL-2R binding. Consequently, overexpression of signaling-deficient, tailless IL-7Ra proteins inhibited IL-2R signaling, demonstrating that IL-7Ra sequesters ?c and suppresses IL-2R signaling by extracellular interactions. Collectively, these results reveal a previously unappreciated regulatory mechanism of IL-2 receptor signaling that is governed by IL-7Ra abundance. Published by Elsevier Inc.

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External Sources

  1. View Full Text
  2. DOI: 10.1016/j.isci.2020.101421
  3. PMID: 32791329
  4. View record in Web of Science®
  5. WOS: 000564160300001
  6. PII : S2589-0042(20)30611-8

Library Notes

  1. Fiscal Year: FY2019-2020
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