Batf-dependent Th17 cells critically regulate IL-23 driven colitis-associated colon cancer

Punkenburg, Elise; Vogler, Tina; Büttner, Maike; Amann, Kerstin; Waldner, MJ; Atreya, Raja; Abendroth, Benjamin; Mudter, Jonas; Merkel, Susanne; Gallmeier, Eike; Rose-John, Stefan; Neurath, Markus F.; Hildner, Kai

doi:10.1136/gutjnl-2014-308227

Cited by 59 publications

(59 citation statements)

References 32 publications

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“…In contrast to these results, another research group found no enhancement in colonic ROR-γT mRNA expression (by quantitative PCR) in patients with active IBD (CD or UC), as well as in those patients with colorectal cancer (Punkenberg et al 2015). The reason(s) for these divergent results are currently unknown.…”

Section: Ror-γt Expression In Human Ibdcontrasting

confidence: 39%

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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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Section: Ror-γt Expression In Human Ibdcontrasting

confidence: 39%

“…The reason(s) for these divergent results are currently unknown. However, different patient populations, as well as methods of ROR-γT quantification, were used in these studies (Martin et al 2015 andPunkenberg et al 2015).…”

Section: Ror-γt Expression In Human Ibdmentioning

confidence: 99%

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

Fitzpatrick

2015

MRAJ

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“…The procedure was performed on mice that were anesthetized by inhalation of ambient air supplemented with 3% isoflurane. Colitis activity was determined by applying a modified murine endoscopic score of colitis severity (MEICS) assessing thickening of the bowel wall, changes in vascularity, granularity of the mucosal surface, and stool consistency, with each scored from 0 to 3, with a maximum total score of 12, as previously described (5).…”

Section: Methodsmentioning

confidence: 99%

“…We have previously identified the AP-1 transcription factor basic leucine zipper transcription factor ATF-like (BATF) to be a critical regulator of Th17 development and a promoter of colitisassociated carcinomas (5,6). Among Th cell subsets, Th17 cells have been implicated in the mediation of tissue destruction in a wide range of inflammatory diseases including inflammatory bowel disease (IBD) (7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

BATF-dependent IL-7RhiGM-CSF+ T cells control intestinal graft-versus-host disease

Ullrich¹,

Abendroth²,

Rothamer³

et al. 2018

Journal of Clinical Investigation

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“…In striking contrast to the plethora of related T helper cell differentiation regulating transcription factors [20][21][22] , Batf seems to lack critical functions outside of T and B cells [18,19] . Interestingly, we recently reported that Batf is strongly upregulated in IBD-affected tissues in an inflammation-dependent fashion suggesting that Batf-expressing T cells are involved in the colitis pathogenesis [23] . To further address this, we studied the role of Batf in the context of intestinal inflammation in mice in more detail.…”

Section: Introductionmentioning

confidence: 99%

Immunopathogenesis of IBD: Batf as a Key Driver of Disease Activity

Hildner

Punkenburg

Abendroth

2016

Dig Dis

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Background: Inflammatory bowel diseases (IBDs) represent a group of chronic immune-mediated disorders that are influenced by a genetic predisposition and additional environmental triggers. Genome-wide association studies strongly implicate that a number of immune system-related genetic variations are critically contributing to the initiation and promotion of intestinal inflammation. Especially the identification of the strong association of a series of single nucleotide polymorphisms including interleukin (IL)-23R, CCR6, signal transducer and activator of transcription 3 (Stat3) and Stat4 with IBD susceptibility point at a critical involvement of T cells and especially of IL-17a-producing Th17 cells in the immune pathogenesis of IBD. In line with this hypothesis, a series of preclinical studies have unequivocally established that T cells are key drivers of immune-mediated colitis. Interestingly, especially Th17 cells were identified to be highly prevalent in inflamed IBD tissues, a finding that seems to be functionally relevant as genetic inactivation studies in the mouse resulted in almost complete suppression of colitis development. Key Messages: While targeting Th17 cell differentiation regulating transcription factors, as retinoic acid-related orphan receptor gamma t (RORγt) is effective in preventing murine colitis, one concern of drugs targeting RORγt in a clinical setting represents the large body of murine data unambiguously demonstrating that additional pathways within and outside the immune system are equally RORγt-dependent increasing the risk of undesirable side effects. The AP1 transcription factor Batf (B cell-activating transcription factor) appears to exclusively regulate pathways within lymphocytes. Importantly, Batf represents a central regulator of Th17 cell development and is strongly upregulated within IBD-affected tissues. Employing 2 acute colitis models, we demonstrate in this study that Batf-expressing T cells are critical drivers of T cell-mediated colitis while in contrast to Stat3 loss of Batf does not affect intestinal epithelial cell homeostasis ex vivo. Conclusions: Targeting Batf in IBD emerges as an attractive therapeutic approach disabling colitogenic T cell activities while sparing off-target effects in the intestinal epithelial cell compartment.

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Batf-dependent Th17 cells critically regulate IL-23 driven colitis-associated colon cancer

Cited by 59 publications

References 32 publications

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

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

BATF-dependent IL-7RhiGM-CSF+ T cells control intestinal graft-versus-host disease

Immunopathogenesis of IBD: Batf as a Key Driver of Disease Activity

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