title: Activated T cells secrete an alternatively spliced form of common γ-chain that inhibits cytokine signaling and exacerbates inflammation.
abstract: The common γ-chain (γc) plays a central role in signaling by IL-2 and other γc-dependent cytokines. Here we report that activated T cells produce an alternatively spliced form of γc mRNA that results in protein expression and secretion of the γc extracellular domain. The soluble form of γc (sγc) is present in serum and directly binds to IL-2Rβ and IL-7Rα proteins on T cells to inhibit cytokine signaling and promote inflammation. sγc suppressed IL-7 signaling to impair naive T cell survival during homeostasis and exacerbated Th17-cell-mediated inflammation by inhibiting IL-2 signaling upon T cell activation. Reciprocally, the severity of Th17-cell-mediated inflammatory diseases was markedly diminished in mice lacking sγc. Thus, sγc expression is a naturally occurring immunomodulator that regulates γc cytokine signaling and controls T cell activation and differentiation.
authors.affiliation: Experimental Immunology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Changwan
authors.initials: C
authors.lastname: Hong
authors.affiliation: Experimental Immunology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Megan A
authors.initials: MA
authors.lastname: Luckey
authors.affiliation: Experimental Immunology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Davinna L
authors.initials: DL
authors.lastname: Ligons
authors.affiliation: Experimental Immunology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Adam T
authors.initials: AT
authors.lastname: Waickman
authors.affiliation: Experimental Immunology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Joo-Young
authors.initials: JY
authors.lastname: Park
authors.affiliation: Experimental Immunology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Grace Y
authors.initials: GY
authors.lastname: Kim
authors.affiliation: Experimental Immunology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Hilary R
authors.initials: HR
authors.lastname: Keller
authors.affiliation: Experimental Immunology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Ruth
authors.initials: R
authors.lastname: Etzensperger
authors.affiliation: Experimental Immunology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Xuguang
authors.initials: X
authors.lastname: Tai
authors.affiliation: Experimental Immunology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Vanja
authors.initials: V
authors.lastname: Lazarevic
authors.affiliation: Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
authors.forename: Lionel
authors.initials: L
authors.lastname: Feigenbaum
authors.affiliation: Clinical and Molecular Retrovirology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.
authors.forename: Marta
authors.initials: M
authors.lastname: Catalfamo
authors.affiliation: Department of Cell Biology and Molecular Genetics, Institute for Bioscience and Biotechnology Research, W. M. Keck Laboratory for Structural Biology, University of Maryland, Rockville, MD 20850, USA.
authors.forename: Scott T R
authors.initials: ST
authors.lastname: Walsh
authors.affiliation: Experimental Immunology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA. Electronic address: parkhy@mail.nih.gov.
authors.forename: Jung-Hyun
authors.initials: JH
authors.lastname: Park
mesh_terms: D017398:Alternative Splicing / Q000276:immunology*; D000818:Animals; D015551:Autoimmunity; D002454:Cell Differentiation / Q000276:immunology; D049109:Cell Proliferation; D002470:Cell Survival / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D007142:Immunoglobulin gamma-Chains / Q000097:blood / Q000235:genetics / Q000276:immunology*; D056747:Immunomodulation; D007249:Inflammation / Q000276:immunology*; D053646:Interleukin-2 Receptor beta Subunit / Q000276:immunology; D053666:Interleukin-5 Receptor alpha Subunit / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011485:Protein Binding / Q000276:immunology; D020033:Protein Isoforms / Q000235:genetics / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology*
chemical_list: C508022:Il2rb protein, mouse; D007142:Immunoglobulin gamma-Chains; D053646:Interleukin-2 Receptor beta Subunit; D053666:Interleukin-5 Receptor alpha Subunit; D020033:Protein Isoforms; D012333:RNA, Messenger