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PMID: 19818650 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural

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

Immunity ·Vol. 31 ·No. 4 ·2009-10-16 ·Pages 587-97

Gomez-Rodriguez J, Sahu N, Handon R, Davidson TS, Anderson SM, Kirby MR, August A, Schwartzberg PL

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.

MeSH Terms
Animals CD4-Positive T-Lymphocytes/immunology,metabolism Calcium/immunology,metabolism Cytokines/immunology,metabolism Interleukin-17/biosynthesis Lung/immunology,pathology Mice Mice, Inbred C57BL Mice, Knockout NFATC Transcription Factors/immunology,metabolism Nuclear Receptor Subfamily 1, Group F, Member 3 Phospholipase C gamma/immunology,metabolism Promoter Regions, Genetic/immunology Protein Serine-Threonine Kinases/genetics,immunology,metabolism Protein-Tyrosine Kinases/genetics,immunology,metabolism Receptors, Antigen, T-Cell/immunology,metabolism Receptors, Retinoic Acid/immunology,metabolism Receptors, Thyroid Hormone/immunology,metabolism Signal Transduction/immunology
Chemicals
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
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Gomez-Rodriguez Julio
National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Sahu Nisebita
Handon Robin
Davidson Todd S
Anderson Stacie M
Kirby Martha R
August Avery
Schwartzberg Pamela L
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Article Info
Journal
Immunity
Abbr.
Immunity
ISSN
1097-4180
DOI
10.1016/j.immuni.2009.07.009
Published
2009-10-16
Epub
2009-00-08
Pages
587-97
Language
English
Region
United States
NLM ID
9432918
PMCID
PMC2767186
Subset
IM
Grants
NIAID NIH HHS · R01 AI051626 · United States
NIAID NIH HHS · R01 AI051626-07 · United States
Intramural NIH HHS · Z01 HG000123-10 · United States
PHS HHS · A1051626 · United States
Corrections
CommentIn
PMID: 19833081
External Links
PubMed source DOI: 10.1016/j.immuni.2009.07.009 PMC Full Text View journal details
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