The Cytokine Receptor IL-7Rα Impairs IL-2 Receptor Signaling and Constrains the In Vitro Differentiation of Foxp3+ Treg Cells
Adam T. Waickman,
Hilary R. Keller,
Tae-Hyoun Kim,
Megan A. Luckey,
Xuguang Tai,
Changwan Hong,
Carmen Molina-París,
Scott T.R. Walsh,
Jung-Hyun Park
Affiliations
Adam T. Waickman
Experimental Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, NIH, Bethesda, MD 20892, USA
Hilary R. Keller
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
Tae-Hyoun Kim
Experimental Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, NIH, Bethesda, MD 20892, USA
Megan A. Luckey
Experimental Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, NIH, Bethesda, MD 20892, USA
Xuguang Tai
Experimental Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, NIH, Bethesda, MD 20892, USA
Changwan Hong
Department of Anatomy, Pusan National University School of Medicine, Yangsan 50612, South Korea
Carmen Molina-París
Department of Applied Mathematics, School of Mathematics, University of Leeds, Leeds, UK
Scott T.R. Walsh
Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, NIH, Frederick, MD 21702, USA
Jung-Hyun Park
Experimental Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, NIH, Bethesda, MD 20892, USA; Corresponding author
Summary: 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-7Rα so that they are impaired in IL-7 signaling. Because Treg cells depend on IL-2, the loss of IL-7Rα has been considered irrelevant for Treg cells. In contrast, here, we report that IL-7Rα downregulation is necessary to maximize IL-2R signaling. Although IL-7Rα overexpression promoted IL-7 signaling, unexpectedly, IL-2 signaling was suppressed in the same cells. Mechanistically, we found that γc, which is a receptor subunit shared by IL-7R and IL-2R, directly binds and pre-associates with IL-7Rα, thus limiting its availability for IL-2R binding. Consequently, overexpression of signaling-deficient, tailless IL-7Rα proteins inhibited IL-2R signaling, demonstrating that IL-7Rα sequesters γc 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-7Rα abundance.
