Differential Expression of Interleukin-17A and -17F Is Coupled to T Cell Receptor Signaling via Inducible T Cell Kinase

National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Immunity (Impact Factor: 19.75). 10/2009; 31(4):587-97. DOI: 10.1016/j.immuni.2009.07.009
Source: PubMed

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.

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Available from: Pamela L Schwartzberg, Jul 23, 2015
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    • "We have previously shown that Itk is a positive regulator of IL17A production and that naive CD4 + T cells from Itkdeficient cells express less IL17A than WT CD4 + T cells under Th17 conditions (Gomez-Rodriguez et al., 2009). To further understand the defect in IL17A expression, we examined the expression of a variety of transcription factors in WT and Itk / cells differentiated under Th17 conditions. "
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    ABSTRACT: A proper balance between Th17 and T regulatory cells (Treg cells) is critical for generating protective immune responses while minimizing autoimmunity. We show that the Tec family kinase Itk (IL2-inducible T cell kinase), a component of T cell receptor (TCR) signaling pathways, influences this balance by regulating cross talk between TCR and cytokine signaling. Under both Th17 and Treg cell differentiation conditions, Itk(-/-) CD4(+) T cells develop higher percentages of functional FoxP3(+) cells, associated with increased sensitivity to IL-2. Itk(-/-) CD4(+) T cells also preferentially develop into Treg cells in vivo. We find that Itk-deficient T cells exhibit reduced TCR-induced phosphorylation of mammalian target of rapamycin (mTOR) targets, accompanied by downstream metabolic alterations. Surprisingly, Itk(-/-) cells also exhibit reduced IL-2-induced mTOR activation, despite increased STAT5 phosphorylation. We demonstrate that in wild-type CD4(+) T cells, TCR stimulation leads to a dose-dependent repression of Pten. However, at low TCR stimulation or in the absence of Itk, Pten is not effectively repressed, thereby uncoupling STAT5 phosphorylation and phosphoinositide-3-kinase (PI3K) pathways. Moreover, Itk-deficient CD4(+) T cells show impaired TCR-mediated induction of Myc and miR-19b, known repressors of Pten. Our results demonstrate that Itk helps orchestrate positive feedback loops integrating multiple T cell signaling pathways, suggesting Itk as a potential target for altering the balance between Th17 and Treg cells.
    Journal of Experimental Medicine 02/2014; 211(3). DOI:10.1084/jem.20131459 · 13.91 Impact Factor
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    • "Although underlying molecular mechanisms have not been described, it is likely that several mediators, such as transcription factor or T cell receptor (TCR) signaling, distinctly regulate the production of the cytokines. Indeed, deficiency of RORa selectively reduced IL-17A production (Yang et al., 2008b), and IL-17A expression was more sensitive to the strength of TCR signaling (Gomez-Rodriguez et al., 2009). "
    Nippon rinsho. Japanese journal of clinical medicine 11/2012; 70 Suppl 8:207-11.
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    • "Th17 subset differentiation, such as the AP-1 transcription factor family member B cell-activating transcription factor (Batf), the Rel/NF-kB member c-Rel, Ikappaz (IkBz) and the Tec family tyrosine kinase member inducible T cell kinase (Itk) [5] [8] [9] [14]. Itk specifically regulates NFATc1 binding to the Il17a promoter and activates the transcription of Il17a but not Il17f, Il17a appears to be the more pathogenic cytokine involved in the autoimmune response [9]. "
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    ABSTRACT: Interleukin-17A (IL-17A) is the signature cytokine produced by Th17 CD4(+) T cells and has been tightly linked to autoimmune pathogenesis. In particular, the transcription factors NFAT and RORγt are known to activate Il17a transcription, although the detailed mechanism of action remains incompletely understood. Here, we show that the nuclear orphan receptor NR2F6 can attenuate the capacity of NFAT to bind to critical regions of the Il17a gene promoter. In addition, because NR2F6 binds to defined hormone response elements (HREs) within the Il17a locus, it interferes with the ability of RORγt to access the DNA. Consistently, NFAT and RORγt binding within the Il17a locus were enhanced in Nr2f6-deficient CD4(+) Th17 cells but decreased in Nr2f6-overexpressing transgenic CD4(+) Th17 cells. Taken together, our findings uncover an example of antagonistic regulation of Il17a transcription through the direct reciprocal actions of NR2F6 versus NFAT and RORγt.
    Journal of Autoimmunity 08/2012; 39(4). DOI:10.1016/j.jaut.2012.07.007 · 7.02 Impact Factor
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