TGF-β Signaling in Dendritic Cells Governs Colonic Homeostasis by Controlling Epithelial Differentiation and the Luminal Microbiota

Ihara, Sigeo; Hirata, Yoshihiro; Serizawa, Takako; Suzuki, Nobumi; Sakitani, Kosuke; Kinoshita, Hiroto; Hayakawa, Yoku; Nakagawa, Hayato; Ijichi, Hideaki; Tateishi, Keisuke; Koike, Kazuhiko

doi:10.4049/jimmunol.1502548

Cited by 36 publications

(31 citation statements)

References 49 publications

(66 reference statements)

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“…We also examined colitis in CD11c-Cre Tgfbr2 fl/fl mice and found enhanced expression of Notch ligands on DCs, goblet cell depletion, a thinner mucus layer, and dysbiosis (Fig. 1b) [50]. These results reveal the critical role played by TGF-b signaling by DCs in colonic homeostasis.…”

Section: Dcsmentioning

confidence: 72%

“…Mice with deletion of TGF-b signaling in DCs (CD11c-Cre Tgfbr2 fl/fl ) developed spontaneous colitis with multiple organ autoimmunity, similar to CD4-Cre Tgfbr2 fl/fl and TGF-b1-null mice [49,50]. Spontaneous colitis in CD11c-Cre Tgfbr2 fl/fl mice was characterized by loss of goblet cells with lymphocytic infiltration and systemic autoimmunity due to altered Treg differentiation, activated T-cells and B-cells, and increased secretion of inflammatory cytokines such as TNF-a and IFN-c [49].…”

Section: Dcsmentioning

confidence: 99%

“…We previously reported overgrowth of Enterobacteriaceae in CD11c-cre Tgfbr2 fl/fl mice. TGF-b signaling of DCs was essential for control of the luminal Enterobacteriaceae through the interactions with epithelial cells [50].…”

Section: Enterobacteriaceaementioning

confidence: 99%

“…TGF-b downregulates the expression of integrin a4b7, E-cadherin, and Jagged1/2 [43,50,55]. Expression of these factors may be upregulated in TGF-b-signaling-impaired IBD patients, and so agents that suppress expression of these factors may have therapeutic potential.…”

Section: Potential Therapeutic Strategies Targeting Tgf-bmentioning

confidence: 99%

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TGF-β in inflammatory bowel disease: a key regulator of immune cells, epithelium, and the intestinal microbiota

2017

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Inflammatory bowel disease (IBD) is defined as chronic intestinal inflammation, and includes ulcerative colitis and Crohn's disease. Multiple factors are involved in the pathogenesis of IBD, and the condition is characterized by aberrant mucosal immune reactions to intestinal microbes in genetically susceptible hosts. Transforming growth factor-b (TGF-b) is an immune-suppressive cytokine produced by many cell types and activated by integrins. Active TGF-b binds to its receptor and regulates mucosal immune reactions through the TGF-b signaling pathway. Dysregulated TGF-b signaling is observed in the intestines of IBD patients. TGF-b signal impairment in specific cell types, such as T-cells and dendritic cells, results in spontaneous colitis in mouse models. In addition, specific intestinal microbes contribute to immune homeostasis by modulating TGF-b production. In this review, we describe the role of TGF-b in intestinal immunity, focusing on immune cells, epithelium, and intestinal microbes. In addition, we present potential therapeutic strategies for IBD that target TGF-b.

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Section: Dcsmentioning

confidence: 72%

Section: Dcsmentioning

confidence: 99%

Section: Enterobacteriaceaementioning

confidence: 99%

Section: Potential Therapeutic Strategies Targeting Tgf-bmentioning

confidence: 99%

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TGF-β in inflammatory bowel disease: a key regulator of immune cells, epithelium, and the intestinal microbiota

2017

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“…Expression of Cre recombinase under the control of the Itgax locus (which encodes CD11c) in CD11c-Cre mice (38) has been used in many studies to conditionally delete the expression of target genes in conventional DC (38–40). Homozygous CXCR5 F/F mice were therefore crossbred to CD11c-Cre mice to generate mice specifically lacking CXCR5 expression in CD11c + conventional DC, termed CXCR5 ΔDC mice here.…”

Section: Resultsmentioning

confidence: 99%

Oral Prion Disease Pathogenesis Is Impeded in the Specific Absence of CXCR5-Expressing Dendritic Cells

Bradford

Reizis

Mabbott

2017

J Virol

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After oral exposure, the early replication of certain prion strains upon stromal cell-derived follicular dendritic cells (FDC) in the Peyer's patches in the small intestine is essential for the efficient spread of disease to the brain. However, little is known of how prions are initially conveyed from the gut lumen to establish infection on FDC. Our previous data suggest that mononuclear phagocytes such as CD11c+ conventional dendritic cells play an important role in the initial propagation of prions from the gut lumen into Peyer's patches. However, whether these cells conveyed orally acquired prions toward FDC within Peyer's patches was not known. The chemokine CXCL13 is expressed by FDC and follicular stromal cells and modulates the homing of CXCR5-expressing cells toward the FDC-containing B cell follicles. Here, novel compound transgenic mice were created in which a CXCR5 deficiency was specifically restricted to CD11c+ cells. These mice were used to determine whether CXCR5-expressing conventional dendritic cells propagate prions toward FDC after oral exposure. Our data show that in the specific absence of CXCR5-expressing conventional dendritic cells the early accumulation of prions upon FDC in Peyer's patches and the spleen was impaired, and disease susceptibility significantly reduced. These data suggest that CXCR5-expressing conventional dendritic cells play an important role in the efficient propagation of orally administered prions toward FDC within Peyer's patches in order to establish host infection.IMPORTANCE Many natural prion diseases are acquired by oral consumption of contaminated food or pasture. Once the prions reach the brain they cause extensive neurodegeneration, which ultimately leads to death. In order for the prions to efficiently spread from the gut to the brain, they first replicate upon follicular dendritic cells within intestinal Peyer's patches. How the prions are first delivered to follicular dendritic cells to establish infection was unknown. Understanding this process is important since treatments which prevent prions from infecting follicular dendritic cells can block their spread to the brain. We created mice in which mobile conventional dendritic cells were unable to migrate toward follicular dendritic cells. In these mice the early accumulation of prions on follicular dendritic cells was impaired and oral prion disease susceptibility was reduced. This suggests that prions exploit conventional dendritic cells to facilitate their initial delivery toward follicular dendritic cells to establish host infection.

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Polyoxazoline‐Based Nanovaccine Synergizes with Tumor‐Associated Macrophage Targeting and Anti‐PD‐1 Immunotherapy against Solid Tumors

et al. 2023

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Immune checkpoint blockade reaches remarkable clinical responses. However, even in the most favorable cases, half of these patients do not benefit from these therapies in the long term. It is hypothesized that the activation of host immunity by co‐delivering peptide antigens, adjuvants, and regulators of the transforming growth factor (TGF)‐β expression using a polyoxazoline (POx)‐poly(lactic‐co‐glycolic) acid (PLGA) nanovaccine, while modulating the tumor‐associated macrophages (TAM) function within the tumor microenvironment (TME) and blocking the anti‐programmed cell death protein 1 (PD‐1) can constitute an alternative approach for cancer immunotherapy. POx‐Mannose (Man) nanovaccines generate antigen‐specific T‐cell responses that control tumor growth to a higher extent than poly(ethylene glycol) (PEG)‐Man nanovaccines. This anti‐tumor effect induced by the POx‐Man nanovaccines is mediated by a CD8+‐T cell‐dependent mechanism, in contrast to the PEG‐Man nanovaccines. POx‐Man nanovaccine combines with pexidartinib, a modulator of the TAM function, restricts the MC38 tumor growth, and synergizes with PD‐1 blockade, controlling MC38 and CT26 tumor growth and survival. This data is further validated in the highly aggressive and poorly immunogenic B16F10 melanoma mouse model. Therefore, the synergistic anti‐tumor effect induced by the combination of nanovaccines with the inhibition of both TAM‐ and PD‐1‐inducing immunosuppression, holds great potential for improving immunotherapy outcomes in solid cancer patients.

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TGF-β Signaling in Dendritic Cells Governs Colonic Homeostasis by Controlling Epithelial Differentiation and the Luminal Microbiota

Cited by 36 publications

References 49 publications

TGF-β in inflammatory bowel disease: a key regulator of immune cells, epithelium, and the intestinal microbiota

TGF-β in inflammatory bowel disease: a key regulator of immune cells, epithelium, and the intestinal microbiota

Oral Prion Disease Pathogenesis Is Impeded in the Specific Absence of CXCR5-Expressing Dendritic Cells

Polyoxazoline‐Based Nanovaccine Synergizes with Tumor‐Associated Macrophage Targeting and Anti‐PD‐1 Immunotherapy against Solid Tumors

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