Human CD1c+ Myeloid Dendritic Cells Acquire a High Level of Retinoic Acid–Producing Capacity in Response to Vitamin D3

Sato, Takayuki; Kitawaki, Toshio; Fujita, Haruyuki; Iwata, Makoto; Iyoda, Tomonori; Inaba, Kayo; Ohteki, Toshiaki; Hasegawa, Suguru; Kawada, Kenji; Sakai, Yoshiharu; Ikeuchi, Hiroki; Nakase, Hiroshi; Niwa, Akira; Takaori‐Kondo, Akifumi; Kadowaki, Norimitsu

doi:10.4049/jimmunol.1203517

Cited by 28 publications

(24 citation statements)

References 40 publications

(69 reference statements)

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“…We therefore speculate that photochemotherapy modulates the homing of the regulatory response induced by the increased apoptosis by the peak of vitamin D 3 it induces [31]. The vitamin D 3 stabilizes the inhibitory function of regulatory T cells and stimulates human dendritic cells to produce retinoic acid, which induces α4β7 gut homing regulatory T cells [32,33,34,35,36]. In humans, α4β7 regulatory T cells are associated with decreased aGvHD of the gut [37].…”

Section: Discussionmentioning

confidence: 99%

Photochemotherapy of Cutaneous Graft-versus-Host Disease May Reduce Concomitant Visceral Disease

Feldreich

Ringdén²,

Emtestam³

et al. 2016

Dermatology

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Background: Photochemotherapy may be used to treat cutaneous graft-versus-host disease (GvHD). Animal models show that in the days after photochemotherapy and antigen provocation, cells with an antigen-specific suppressive phenotype are elicited in the lymphoid organs. In GvHD, host antigens are present not only in the skin treated by photochemotherapy but also in the visceral tissues. Objective: The aim of this paper was to evaluate the effect on visceral acute GvHD (aGvHD) of photochemotherapy of the skin. Methods: We retrospectively evaluated 33 patients with aGvHD of the skin, the liver, and/or the gastrointestinal tract treated with photochemotherapy for their aGvHD of the skin and did a long-term follow-up of 10 years on survival. Results: The complete response (CR) to photochemotherapy was 39%, the complete and partial response was 64% and the 6-month survival was 64%. Total body irradiation (TBI) before hematopoietic stem cell transplantation predisposed for CR of aGvHD of the liver and the gastrointestinal tract (p = 0.045). In the TBI group, the accumulated dose (numbers of treatments) for CR of visceral aGvHD increased with the body surface area affected by disease, from 8 (min-max: 5-14) for skin disease stage 1 to 10.5 (6-33) for stage 2 and 13 (11-21) for stage 3 (p = 0.04). Skin disease stage 1 showed a trend to be associated with CR in visceral disease at 28, 56, and 100 days (p = 0.07). Overall CR in visceral disease predicted a better 10-year overall survival (p = 0.0036). Finally, after TBI aGvHD of the gastrointestinal tract without anti-thymocyte globulin (ATG), clearance of T cells and dendritic cells responded better than aGvHD of the liver and aGvHD of the gastrointestinal tract with ATG (p = 0.01). Conclusion: Photochemotherapy after ionizing irradiation regulates the cell-mediated immunity in the viscera, and the systemic efficacy increases when the skin itself is less affected by disease. ATG modulates the regulatory effect of the gastrointestinal tract.

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Section: Discussionmentioning

confidence: 99%

Photochemotherapy of Cutaneous Graft-versus-Host Disease May Reduce Concomitant Visceral Disease

Feldreich

Ringdén²,

Emtestam³

et al. 2016

Dermatology

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“…GM-CSF and RA are involved in RALDH2 expression not only in mouse DCs but also in human DCs [38], [39]. In small intestine tissues and MLNs, GM-CSF is produced by various types of cells, including epithelial cells, Paneth cells, macrophages, and T cells, while RA may be produced by some types of cells including RALDH1 + intestinal epithelial cells, RALDH2 + cDCs, and Aldh1a1 + Aldh1a2 + Aldh1a3 + MLN stromal cells [1], [19], [40]–[43].…”

Section: Discussionmentioning

confidence: 99%

Retinoic Acid and GM-CSF Coordinately Induce Retinal Dehydrogenase 2 (RALDH2) Expression through Cooperation between the RAR/RXR Complex and Sp1 in Dendritic Cells

et al. 2014

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Retinoic acid (RA)-producing dendritic cells (DCs) play critical roles in gut immunity. Retinal dehydrogenase 2 (RALDH2) encoded by Aldh1a2 is a key enzyme for generating RA in DCs. Granulocyte–macrophage colony-stimulating factor (GM-CSF) potently induces RALDH2 expression in DCs in an RA-dependent manner, and RA alone weakly induces the expression. However, how GM-CSF and RA induce RALDH2 expression remains unclear. Here, we show that GM-CSF-induced activation of the transcription factor Sp1 and RA-dependent signaling via the RA receptor (RAR)/retinoid X receptor (RXR) complex contribute to Aldh1a2 expression. The RAR antagonist LE540 and the Sp1 inhibitor mithramycin A inhibited GM-CSF-induced Aldh1a2 expression in fms-related tyrosine kinase 3 ligand-generated bone marrow-derived DCs (BM-DCs). ERK and p38 MAPK inhibitors suppressed GM-CSF-induced nuclear translocation of Sp1 and Aldh1a2 expression. Sp1 and the RARα/RXRα complex bound to GC-rich Sp1-binding sites and an RA response element (RARE) half-site, respectively, near the TATA box in the mouse Aldh1a2 promoter. The DNA sequences around these sites were highly conserved among different species. In the presence of RA, ectopic expression of RARα/RXRα and Sp1 synergistically enhanced Aldh1a2 promoter-reporter activity. GM-CSF did not significantly induce Aldh1a2 expression in plasmacytoid DCs, peritoneal macrophages, or T cells, and the Aldh1a2 promoter in these cells was mostly unmethylated. These results suggest that GM-CSF/RA-induced RALDH2 expression in DCs requires cooperative binding of Sp1 and the RAR/RXR complex to the Aldh1a2 promoter, and can be regulated by a DNA methylation-independent mechanism.

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“…DC induce naïve CD4 ? T cells to produce high IL-4, IL-5, IL-13 and IL-10 in vitro, although suppressive capacity of these cells could not be confirmed [96]. High expression of regulatory molecules ILT4, ICOS-L and PD-L1, production of IL-10 and differentiation of IL-10 secreting suppressive T cells by CD1c ?…”

Section: The Role Of Cd1c 1 DC In Immune Regulationmentioning

confidence: 93%

“…CD1c ? DC express high levels of RALDH2, particularly in response to known immunosuppressive factors such as, 1a,25-dihydroxyvitamin D3 (Vitamin D 3 ) and this is exacerbated by RA, which is also expressed by intestinal epithelial cells [96]. RALDH2 expressing CD1c ?…”

Section: The Role Of Cd1c 1 DC In Immune Regulationmentioning

confidence: 99%

Human dendritic cell subsets and function in health and disease

O’Keeffe

Mok

Radford

2015

Cell. Mol. Life Sci.

163

149

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The method of choice for the development of new vaccines is to target distinct dendritic cell subsets with antigen in vivo and to harness their function in situ to enhance cell-mediated immunity or induce tolerance to specific antigens. The innate functions of dendritic cells themselves may also be targeted by inhibitors or activators that would target a specific function such as interferon production, potentially important in autoimmune disease and chronic viral infections. Importantly targeting dendritic cells requires detailed knowledge of both the surface phenotype and function of each dendritic cell subset, including how they may respond to different types of vaccine adjuvants, their ability to produce soluble mediators and to process and present antigens and induce priming of naïve T cells. This review summarizes our knowledge of the functional attributes of the human dendritic cell subsets in the steady state and upon activation and their roles in human disease.

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Human CD1c+ Myeloid Dendritic Cells Acquire a High Level of Retinoic Acid–Producing Capacity in Response to Vitamin D3

Cited by 28 publications

References 40 publications

Photochemotherapy of Cutaneous Graft-versus-Host Disease May Reduce Concomitant Visceral Disease

Photochemotherapy of Cutaneous Graft-versus-Host Disease May Reduce Concomitant Visceral Disease

Retinoic Acid and GM-CSF Coordinately Induce Retinal Dehydrogenase 2 (RALDH2) Expression through Cooperation between the RAR/RXR Complex and Sp1 in Dendritic Cells

Human dendritic cell subsets and function in health and disease

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