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.
Copyright © 2014 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
MeSH terms
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Alternative Splicing / immunology*
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Animals
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Autoimmunity
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Cell Differentiation / immunology
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Cell Proliferation
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Cell Survival / immunology
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Encephalomyelitis, Autoimmune, Experimental / immunology*
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Immunoglobulin gamma-Chains / blood
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Immunoglobulin gamma-Chains / genetics
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Immunoglobulin gamma-Chains / immunology*
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Immunomodulation
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Inflammation / immunology*
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Interleukin-2 Receptor beta Subunit / immunology
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Interleukin-5 Receptor alpha Subunit / immunology
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Lymphocyte Activation / immunology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Protein Binding / immunology
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Protein Isoforms / genetics
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Protein Isoforms / immunology
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics
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Signal Transduction / immunology
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Th17 Cells / immunology*
Substances
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Il2rb protein, mouse
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Immunoglobulin gamma-Chains
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Interleukin-2 Receptor beta Subunit
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Interleukin-5 Receptor alpha Subunit
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Protein Isoforms
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RNA, Messenger