Transcriptional regulatory networks in Th17 cell differentiation

Zhou, Liang; Littman, Dan R.

doi:10.1016/j.coi.2009.03.001

Cited by 167 publications

(135 citation statements)

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“…This leads to homodimerization and translocation of STAT3 into the nucleus, where STAT3 directly binds to the il17a promoter and is required for the induction of ROR␥t. 17,19 Consistent with this, STAT3 Ϫ/Ϫ mice completely lack Th17 cells and are resistant to experimental autoimmune encephalitis. To date, a network of transcription factors has been linked to Th17 differentiation, yet modifiers of the signaling cascade from cytokine stimulation to transcription, and in turn Th17 development, are not well understood.…”

Section: Introductionsupporting

confidence: 50%

“…2,9,12,17,18 The signaling cascade via the IL-6 receptor leads to the downstream activation of Jak kinases and, in turn, Jak-mediated phosphorylation of STAT3 proteins. This leads to homodimerization and translocation of STAT3 into the nucleus, where STAT3 directly binds to the il17a promoter and is required for the induction of ROR␥t.…”

Section: Introductionmentioning

confidence: 99%

“…IL-6 stimulation has been shown to induce the activation of the Jak/STAT3 pathway, which in turn directly regulates ROR␥t and ROR␣ activation and Th17 cell differentiation. 2,9,12,17,18 To address whether SHP-1 is a negative regulator of Jak/STAT3 signaling, purified CD4 ϩ T cells from ϩ/ϩ, me/ϩ, and me/me mice were stimulated with IL-6 and examined for levels of induced STAT3 phosphorylation as an indicator of STAT3 activation. 19 We made 2 key observations.…”

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confidence: 99%

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The tyrosine phosphatase SHP-1 dampens murine Th17 development

Mauldin

Tung

Lorenz

2012

Blood

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IntroductionTh17 cells are a subset of CD4 ϩ T helper cells defined by their ability to secrete IL-17A and IL-17F. 1,2 IL-17 is an inflammatory cytokine important in mediating host defense against bacterial and fungal pathogens. 3,4 Under physiologic conditions, Th17 cells are found in the intestinal lamina propria and Peyer patches, where they are regulated by the local cytokine milieu and support responses against pathogenic bacteria and fungi. [5][6][7][8] However, unregulated Th17 development and IL-17 production have been shown to contribute to the development of allergic and autoimmune diseases. 1,[9][10][11][12] Recently, Th17 cells have also been linked to cancer, but their involvement toward cancer ablation or progression varies widely depending on the type of cancer. [13][14][15][16] Therefore, characterizing the intracellular signaling within CD4 ϩ T cells that modifies Th17 development will have important clinical implications for a broad range of diseases. To date, few studies have addressed how modifying early signaling events in CD4 ϩ T cells affects Th17 differentiation.Stimulation of naive T cells with either IL-6 plus TGF-␤ or IL-21 plus TGF-␤ leads to the activation and induction of several key transcription factors essential for Th17 differentiation, including STAT3, ROR␥t, and ROR␣. 2,9,12,17,18 The signaling cascade via the IL-6 receptor leads to the downstream activation of Jak kinases and, in turn, Jak-mediated phosphorylation of STAT3 proteins. This leads to homodimerization and translocation of STAT3 into the nucleus, where STAT3 directly binds to the il17a promoter and is required for the induction of ROR␥t. 17,19 Consistent with this, STAT3 Ϫ/Ϫ mice completely lack Th17 cells and are resistant to experimental autoimmune encephalitis. To date, a network of transcription factors has been linked to Th17 differentiation, yet modifiers of the signaling cascade from cytokine stimulation to transcription, and in turn Th17 development, are not well understood. 20 The Src homology region 2 domain-containing tyrosine phosphatase-1 (SHP-1) is a cytoplasmic protein tyrosine phosphatase expressed in all hematopoietic cell lineages. Motheaten (me/me) mice are homozygous for a mutation that abrogates SHP-1 protein expression and display hematopoietic abnormalities resulting in death approximately 2 to 3 weeks after birth. SHP-1 is a negative regulator of signaling via cytokines, chemokines, growth factors, and antigens. 21 Specifically, SHP-1-deficient T cells display increased responses to TCR stimulation and concomitant hyperproliferation in ex vivo cultures. 22 However, the role of SHP-1 during Th17 cell differentiation is not known. Here, using mice in the motheaten background, as well as a new tissue-specific transgenic mouse line expressing a dominant negative mutant of SHP-1 in T cells, we demonstrate that SHP-1 naturally dampens Th17 cell development in vivo. SHP-1-deficient mice have increased percentages of Th17 cells in their Peyer patches and intestinal lamina propria, and T cells with d...

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Section: Introductionsupporting

confidence: 50%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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The tyrosine phosphatase SHP-1 dampens murine Th17 development

Mauldin

Tung

Lorenz

2012

Blood

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“…Recently, a new subset of CD4ϩ T cells, Th17 cells, was reported to have an essential role in dampening local inflammation (11)(12)(13). Th17 cells produce proinflammatory molecules, IL-17, IL-17F, and IL-22, which act on tissue resident cells to promote inflammation.…”

mentioning

confidence: 99%

Vitamin D Suppresses Th17 Cytokine Production by Inducing C/EBP Homologous Protein (CHOP) Expression

Chang

Chung²,

Dong

2010

Journal of Biological Chemistry

168

130

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Vitamin D is an essential nutrient that regulates calcium and phosphate transport and bone mineralization (1). In recent years, however, vitamin D has been found to have a much broader range of actions, including regulation of cell differentiation, proliferation, and apoptosis (2). The role of vitamin D in immune system is complex and diverse. The systemic or locally produced active form of vitamin D, 1,25-dihydroxyvitamin D 3 (1,25D3), 3 can exercise its effects on several immune cells, including macrophages, dendritic cells, and T and B cells. Several reports indicated that 1,25D3 can act directly on T cells or indirectly on dendritic cells to modulate T cell function (3-6). However, the concentrations of 1,25D3 employed in many studies are often above the physiological range, bringing into question the physiological relevance of the effect of 1,25D3 on T cells. Nonetheless, modulation of CD4ϩ T cells by 1,25D3 is intriguing because several studies have demonstrated that 1,25D3 is capable of suppressing inflammation in vivo (7-10).Recently, a new subset of CD4ϩ T cells, Th17 cells, was reported to have an essential role in dampening local inflammation (11-13). Th17 cells produce proinflammatory molecules, IL-17, IL-17F, and IL-22, which act on tissue resident cells to promote inflammation. TGF␤ and IL-6 are critical in generation of Th17 cells by activating STAT3 and inducing the transcription factors, retinoic acid-related orphan receptor (ROR␥t) (14) and ROR␣ (15). IL-1 and IL-23 are also important cytokines to stabilize and maintain Th17 cells (16,17). Therefore, pathways to regulate Th17 cell development and its cytokines are relevant. Of interest, a previous report indicated that 1,25D3 is able to prevent experimental autoimmune uveitis, partially because of its suppressive effect directly on Th17 cells (10). However, it is not known whether the effect is mediated through vitamin D receptor (VDR) and how 1,25D3 suppresses IL-17 and other Th17 cytokine production in T cells.In this study, we have examined the mechanism whereby 1,25D3 regulates CD4ϩ T cell function at physiological concentrations. We found that in response to 1,25D3, Th17 cells produced reduced levels of cytokines at the protein level, whereas their transcriptions were not affected. Moreover, 1,25D3 treatment in Th17 cells induced the expression of C/EBP homologous protein (CHOP). Overexpression of CHOP in Th17 cells suppressed their cytokine production. Our data thus suggest a post-transcriptional inhibition of Th17 cell function by VDR. EXPERIMENTAL PROCEDURESMice-C57Bl/6-and VDR-deficient mice were purchased from The Jackson Laboratory, and 6 -8-week-old mice were used in experiments. Mice were housed in the specific pathogen-free animal facility at MD Anderson Cancer Center, and the animal experiments were performed using protocols approved by the Institutional Animal Care and Use Committee.Th Cell Differentiation-Naive CD4lo T cells from C57Bl/6 mice were FACS-sorted and stimulated with plate-bound anti-CD3 (0.5 g/ml) plus soluble anti...

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“…Retinoic Acid Related Orphan Nuclear Receptor gamma T (ROR-γT) is the lineage specifying transcription factor for IL-17 expressing cells such as Thelper cell 17 (Th17), and gamma-delta (γδ) T cells (Zhou and Littman 2009, Kanai et al 2012and Fitzpatrick et al 2015.…”

Section: Introductionmentioning

confidence: 99%

Ror-gamma T inhibition as a Pharmacological Approach for Inflammatory Bowel Disease

Fitzpatrick

2015

MRAJ

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Retinoic Acid Related Orphan Nuclear Receptor gamma T (ROR-γT) is the lineage specifying transcription factor for IL-17 expressing cells. ROR-γT expression is up-regulated in various animal models of colitis, as well as in certain patients with Inflammatory Bowel Disease (IBD). Transfer of ROR-gamma null T cells to RAG1 deficient mice did not induce colitis in these animals. Recently, data with a specific small molecule inhibitor (VPR-7) of ROR-γT showed efficacy in a murine model of IBD.In principle, ROR-γT inhibitors would specifically inhibit Th17 cell differentiation and expansion. ROR-γT, which is functioning in innate intestinal lymphoid cells, may also be a target for ROR-γT inhibitors. These drugs would block the transcription of possible pro-inflammatory receptors (IL-23R) cytokines (IL-17, IL-21) and chemokines (CCL20) putatively involved in the pathogenesis of IBD. Off-target effects of ROR-γT inhibitors have been reported, including the inhibition of colonic IL-23 in a mouse model of colitis. Several pharmaceutical companies are actively involved in the development of specific inhibitors targeting ROR-γT. It is possible that ROR-γT inhibitors will enter clinical trials for the treatment of IBD in the near future.

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Transcriptional regulatory networks in Th17 cell differentiation

Cited by 167 publications

References 64 publications

The tyrosine phosphatase SHP-1 dampens murine Th17 development

The tyrosine phosphatase SHP-1 dampens murine Th17 development

Vitamin D Suppresses Th17 Cytokine Production by Inducing C/EBP Homologous Protein (CHOP) Expression

Ror-gamma T inhibition as a Pharmacological Approach for Inflammatory Bowel Disease

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