Abstract
Invariant natural killer T (iNKT) cells have the ability to rapidly secret cytokines in response to diverse stimuli, and therefore influence numerous immune reactions. Although IFN-γ and IL-4 are thought to dominate iNKT cytokine production, a distinct subset of iNKT cells, expressing RORγt and producing IL-17, has now been identified in both mice and humans. Although a role in pathogen and allergic responses has been assigned to the RORγt(+) iNKT subset, factors controlling their development and function remain illusive. Here, we demonstrate that RORγt(+) iNKT-cell differentiation obeys transforming growth factor-β (TGF-β) signaling control, different from that described for conventional iNKT cells. We reveal that TGF-β signaling, and particularly its SMAD4-dependent pathway, is required for both the survival of RORγt(+) iNKT cells during their development and IL-17 production at the periphery. Moreover, constitutive TGF-β signaling in RORγt(+) iNKT cells drives higher peripheral numbers and increased tissue distribution. Finally, we found that SMAD4-dependent TGF-β signaling is mandatory for the peripheral expansion of the RORγt(+) iNKT cells responding to inflammatory signals. Thus, this work demonstrates that both the development and responsiveness of the newly described IL-17-producing iNKT cell subset is under the control of a dedicated TGF-β signaling pathway.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / genetics
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Apoptosis / physiology
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Cell Differentiation* / drug effects
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Cell Differentiation* / genetics
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Cell Differentiation* / immunology
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Cell Proliferation / drug effects
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Interleukin-17 / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Natural Killer T-Cells / drug effects
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Natural Killer T-Cells / immunology*
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Natural Killer T-Cells / metabolism
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Natural Killer T-Cells / physiology*
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Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism*
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Protein Serine-Threonine Kinases / physiology
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Receptor, Transforming Growth Factor-beta Type II
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Receptors, Transforming Growth Factor beta / genetics
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Receptors, Transforming Growth Factor beta / metabolism
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Receptors, Transforming Growth Factor beta / physiology
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Signal Transduction / genetics
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Signal Transduction / immunology
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Signal Transduction / physiology
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Smad4 Protein / genetics
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Smad4 Protein / metabolism
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Thymocytes / metabolism
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Thymocytes / physiology
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Thymus Gland / cytology
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Thymus Gland / drug effects
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Thymus Gland / metabolism
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Thymus Gland / physiology
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Transforming Growth Factor beta / metabolism
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Transforming Growth Factor beta / pharmacology
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Transforming Growth Factor beta / physiology*
Substances
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Il17a protein, mouse
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Interleukin-17
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Nuclear Receptor Subfamily 1, Group F, Member 3
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Receptors, Transforming Growth Factor beta
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Smad4 Protein
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Smad4 protein, mouse
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Transforming Growth Factor beta
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Protein Serine-Threonine Kinases
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Receptor, Transforming Growth Factor-beta Type II