Notch Balances Th17 and Induced Regulatory T Cell Functions in Dendritic Cells by Regulating Aldh1a2 Expression

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書誌事項

タイトル
Notch Balances Th17 and Induced Regulatory T Cell Functions in Dendritic Cells by Regulating Aldh1a2 Expression
タイトル別名
  • NotchタンパクはAldh1a2遺伝子の発現を調整することで、樹状細胞のTh17細胞誘導と誘導性制御性T細胞誘導の平衡を保っている
  • Notch AND Aldh1a2 REGULATION IN DCs
著者
ザマン, タスキア サルタナ
著者別名
  • Zaman, Taskia Sultana
著者
有持, 秀喜
著者別名
  • アリモチ, ヒデキ
  • Arimochi, Hideki
著者
マルヤマ, サトシ
著者別名
  • Maruyama, Satoshi
著者
石舟, 智恵子
著者別名
  • イシフネ, チエコ
  • Ishifune, Chieko
著者
九十九, 伸一
著者別名
  • ツクモ, シンイチ
  • Tsukumo, Shin-ichi
著者
北村, 明子
著者別名
  • キタムラ, アキコ
  • Kitamura, Akiko
著者
安友, 康二
著者別名
  • ヤストモ, コウジ
  • Yasutomo, Koji
学位授与大学
徳島大学
取得学位
博士（医学）
学位授与番号
甲医第1344号
学位授与年月日
2017-09-28

説明

Dendritic cells (DCs) are important for adaptive immune responses through the activation of T cells. The molecular interplay between DCs and T cells determines the magnitude of T cell responses or outcomes of functional differentiation of T cells. In this study, we demonstrated that DCs in mice that are Rbpj deficient in CD11c+ cells (Rbpj−/− mice) promoted the differentiation of IL-17A–producing Th17 cells. Rbpj-deficient DCs expressed little Aldh1a2 protein that is required for generating retinoic acid. Those DCs exhibited a reduced ability for differentiating regulatory T cells induced by TGF-β. Rbpj protein directly regulated Aldh1a2 transcription by binding to its promoter region. The overexpression of Aldh1a2 in Rbpj-deficient DCs negated their Th17-promoting ability. Transfer of naive CD4+ T cells into Rag1-deficient Rbpj−/− mice enhanced colitis with increased Th17 and reduced induced regulatory T cells (iTreg) compared with control Rag1-deficient mice. The cotransfer of iTreg and naive CD4+ T cells into Rag1-deficient Rbpj−/− mice improved colitis compared with transfer of naive CD4+ T cell alone. Furthermore, cotransfer of DCs from Rbpj−/− mice that overexpressed Aldh1a2 or Notch-stimulated DCs together with naive CD4+ T cells into Rbpj−/− Rag1-deficient mice led to reduced colitis with increased iTreg numbers. Therefore, our studies identify Notch signaling in DCs as a crucial balancer of Th17/iTreg, which depends on the direct regulation of Aldh1a2 transcription in DCs.

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