TY - JOUR
T1 - Differential Expression of Interleukin-17A and -17F Is Coupled to T Cell Receptor Signaling via Inducible T Cell Kinase
AU - Gomez-Rodriguez, Julio
AU - Sahu, Nisebita
AU - Handon, Robin
AU - Davidson, Todd S.
AU - Anderson, Stacie M.
AU - Kirby, Martha R.
AU - August, Avery
AU - Schwartzberg, Pamela L.
N1 - Funding Information:
We would like to thank the Schwartzberg laboratory, J. Zhu, H. Yamane and J. Cote-Sierra for advice and helpful discussions; D. Littman, N. Clipstone, and L. Berg for retroviral constructs and mice, J. Fekecs and D. Leja for graphics assistance, and J. O'Shea, J. Zhu, J. Cannons and W. Paul for critical reading of the manuscript. This work was supported by funding from the intramural research program of the NHGRI, NIH (to PLS) and NIH grant A1051626 (to AA).
PY - 2009/10/16
Y1 - 2009/10/16
N2 - 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-γ (PLC-γ1) activation, exhibit decreased interleukin-17A (IL-17A) expression in vitro and in vivo, despite relatively normal expression of retinoic acid receptor-related orphan receptor-γT (ROR-γT) and IL-17F. IL-17A expression was rescued by pharmacologically induced Ca2+ 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.
AB - 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-γ (PLC-γ1) activation, exhibit decreased interleukin-17A (IL-17A) expression in vitro and in vivo, despite relatively normal expression of retinoic acid receptor-related orphan receptor-γT (ROR-γT) and IL-17F. IL-17A expression was rescued by pharmacologically induced Ca2+ 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.
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U2 - 10.1016/j.immuni.2009.07.009
DO - 10.1016/j.immuni.2009.07.009
M3 - Article
C2 - 19818650
AN - SCOPUS:70349743977
SN - 1074-7613
VL - 31
SP - 587
EP - 597
JO - Immunity
JF - Immunity
IS - 4
ER -
