Development and function of murine RORγt+ iNKT cells are under TGF-β signaling control

Blood. 2012 Apr 12;119(15):3486-94. doi: 10.1182/blood-2012-01-401604. Epub 2012 Feb 27.


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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Apoptosis / physiology
  • Cell Differentiation* / drug effects
  • Cell Differentiation* / genetics
  • Cell Differentiation* / immunology
  • Cell Proliferation / drug effects
  • Interleukin-17 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Natural Killer T-Cells / drug effects
  • Natural Killer T-Cells / immunology*
  • Natural Killer T-Cells / metabolism
  • Natural Killer T-Cells / physiology*
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism*
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Protein Serine-Threonine Kinases / physiology
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / genetics
  • Receptors, Transforming Growth Factor beta / metabolism
  • Receptors, Transforming Growth Factor beta / physiology
  • Signal Transduction / genetics
  • Signal Transduction / immunology
  • Signal Transduction / physiology
  • Smad4 Protein / genetics
  • Smad4 Protein / metabolism
  • Thymocytes / metabolism
  • Thymocytes / physiology
  • Thymus Gland / cytology
  • Thymus Gland / drug effects
  • Thymus Gland / metabolism
  • Thymus Gland / physiology
  • Transforming Growth Factor beta / metabolism
  • Transforming Growth Factor beta / pharmacology
  • Transforming Growth Factor beta / physiology*


  • Il17a protein, mouse
  • Interleukin-17
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • Receptors, Transforming Growth Factor beta
  • Smad4 Protein
  • Smad4 protein, mouse
  • Transforming Growth Factor beta
  • Protein Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II