Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
J Immunol. 2013 Sep 15;191(6):3152-60. doi: 10.4049/jimmunol.1203517. Epub 2013 Aug 21.
All-trans-retinoic acid (RA) plays a critical role in maintaining immune homeostasis. Mouse intestinal CD103⁺ dendritic cells (DCs) produce a high level of RA by highly expressing retinal dehydrogenase (RALDH)2, an enzyme that converts retinal to RA, and induce gut-homing T cells. However, it has not been identified which subset of human DCs produce a high level of RA. In this study, we show that CD1c⁺ blood myeloid DCs (mDCs) but not CD141(high) mDCs or plasmacytoid DCs exhibited a high level of RALDH2 mRNA and aldehyde dehydrogenase (ALDH) activity in an RA- and p38-dependent manner when stimulated with 1α,25-dihydroxyvitamin D₃ (VD₃) in the presence of GM-CSF. The ALDH activity was abrogated by TLR ligands or TNF. CD103⁻ rather than CD103⁺ human mesenteric lymph node mDCs gained ALDH activity in response to VD₃. Furthermore, unlike in humans, mouse conventional DCs in the spleen and mesenteric lymph nodes gained ALDH activity in response to GM-CSF alone. RALDH2(high) CD1c⁺ mDCs stimulated naive CD4⁺ T cells to express gut-homing molecules and to produce Th2 cytokines in an RA-dependent manner. This study suggests that CD1c⁺ mDCs are a major human DC subset that produces RA in response to VD₃ in the steady state. The "vitamin D-CD1c⁺mDC-RA" axis may constitute an important immune component for maintaining tissue homeostasis in humans.
全反式视黄酸（RA）在维持免疫稳态中起着关键作用。小鼠肠道 CD103⁺树突状细胞（DC）通过高度表达视网膜脱氢酶（RALDH）2 产生高水平的 RA，RALDH2 是一种将视黄醛转化为 RA 的酶，并诱导肠道归巢 T 细胞。然而，尚未确定人类 DC 的哪个亚群产生高水平的 RA。在这项研究中，我们表明，在 GM-CSF 存在下，用 1α，25-二羟维生素 D₃（VD₃）刺激时，CD1c⁺血液髓样 DC（mDC）而非 CD141（高）mDC 或浆细胞样 DC 以 RA 和 p38 依赖的方式表现出高水平的 RALDH2 mRNA 和醛脱氢酶（ALDH）活性。TLR 配体或 TNF 可阻断 ALDH 活性。CD103⁻而非 CD103⁺人肠系膜淋巴结 mDC 对 VD₃ 反应获得 ALDH 活性。此外，与人类不同，脾脏和肠系膜淋巴结中的鼠常规 DC 仅对 GM-CSF 有反应即可获得 ALDH 活性。RALDH2（高）CD1c⁺mDC 以 RA 依赖的方式刺激幼稚 CD4⁺T 细胞表达肠道归巢分子并产生 Th2 细胞因子。这项研究表明，CD1c⁺mDC 是人类中主要的 DC 亚群，它在稳态下响应 VD₃ 产生 RA。“维生素 D-CD1c⁺mDC-RA”轴可能构成维持人类组织稳态的重要免疫成分。
