Differential expression of interleukin-17A and -17F is coupled to T cell receptor signaling via inducible T cell kinase.
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.
Gomez-Rodriguez
Julio
J
National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Sahu
Nisebita
N
Handon
Robin
R
Davidson
Todd S
TS
Anderson
Stacie M
SM
Kirby
Martha R
MR
August
Avery
A
Schwartzberg
Pamela L
PL
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002118:Calcium / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000276:immunology* / Q000378:metabolism; D020381:Interleukin-17 / Q000096:biosynthesis*; D008168:Lung / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050778:NFATC Transcription Factors / Q000276:immunology / Q000378:metabolism; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D051966:Phospholipase C gamma / Q000276:immunology / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000276:immunology / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology
D016207:Cytokines; D020381:Interleukin-17; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C539900:RORC protein, human; D011948:Receptors, Antigen, T-Cell; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; C539901:Rorc protein, mouse; D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase; D017346:Protein Serine-Threonine Kinases; D051966:Phospholipase C gamma; D002118:Calcium