Differential expression of interleukin-17A and -17F is coupled to T cell receptor signaling via inducible T cell kinase

Immunity. 2009 Oct 16;31(4):587-97. doi: 10.1016/j.immuni.2009.07.009. Epub 2009 Oct 8.

Abstract

T helper 17 (Th17) cells play major roles in autoimmunity and bacterial infections, yet how T cell receptor (TCR) signaling affects Th17 cell differentiation is relatively unknown. We demonstrate that CD4(+) T cells lacking Itk, a tyrosine kinase required for full TCR-induced phospholipase C-gamma (PLC-gamma1) activation, exhibit decreased interleukin-17A (IL-17A) expression in vitro and in vivo, despite relatively normal expression of retinoic acid receptor-related orphan receptor-gammaT (ROR-gammaT) and IL-17F. IL-17A expression was rescued by pharmacologically induced Ca(2+) influx or constitutively activated nuclear factor of activated T cells (NFAT). Conversely, decreased TCR stimulation or calcineurin inhibition preferentially reduced IL-17A expression. We further found that the promoter of Il17a but not Il17f has a conserved NFAT binding site that bound NFATc1 in wild-type but not Itk-deficient cells, even though both exhibited open chromatin conformations. Finally, Itk(-/-) mice also showed differential regulation of IL-17A and IL-17F in vivo. Our results suggest that Itk specifically couples TCR signaling to Il17a expression and the differential regulation of Th17 cell cytokines through NFATc1.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • Calcium / immunology
  • Calcium / metabolism
  • Cytokines / immunology*
  • Cytokines / metabolism
  • Interleukin-17 / biosynthesis*
  • Lung / immunology
  • Lung / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NFATC Transcription Factors / immunology
  • NFATC Transcription Factors / metabolism
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • Phospholipase C gamma / immunology
  • Phospholipase C gamma / metabolism
  • Promoter Regions, Genetic / immunology
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / immunology
  • Protein-Serine-Threonine Kinases / metabolism*
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / immunology
  • Protein-Tyrosine Kinases / metabolism*
  • Receptors, Antigen, T-Cell / immunology
  • Receptors, Antigen, T-Cell / metabolism
  • Receptors, Retinoic Acid / immunology
  • Receptors, Retinoic Acid / metabolism
  • Receptors, Thyroid Hormone / immunology
  • Receptors, Thyroid Hormone / metabolism
  • Signal Transduction / immunology

Substances

  • Cytokines
  • Interleukin-17
  • NFATC Transcription Factors
  • Nfatc1 protein, mouse
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • RORC protein, human
  • Receptors, Antigen, T-Cell
  • Receptors, Retinoic Acid
  • Receptors, Thyroid Hormone
  • Rorc protein, mouse
  • Protein-Tyrosine Kinases
  • emt protein-tyrosine kinase
  • Protein-Serine-Threonine Kinases
  • Phospholipase C gamma
  • Calcium