低酸素誘導因子1によるT (H) 17/T (Reg) バランスの制御

Eric V Dang¹, Joseph Barbi, Huang-Yu Yang

¹Immunology and Hematopoiesis Division, Department of Oncology and Medicine, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Maryland 21231, USA.

Cell

|August 30, 2011

まとめ

低酸素誘導因子1 (HIF-1) は,T細胞の分化を制御し,T細胞を促進し,T細胞を抑制しながら,T細胞を抑制する. メタボリック要因はT細胞の運命を左右し,免疫疾患の潜在的治療標的となる.

科学分野:

免疫学免疫学とは
メタボリック・レギュレーション
細胞の微分化は

背景:

T細胞がエフェクタとレギュレータサブセットに分離することは,免疫ホメオスタシスにとって極めて重要です.
サイトカイン環境と代謝状態は,T細胞の運命決定に影響を与えます.
調節性T細胞 (T(reg)) は免疫反応を抑制し,T(H) 17細胞は炎症を促進する.

研究の目的:

低酸素誘導因子1 (HIF-1) がT(reg) とT(H) 17細胞の分化間のバランスを調節する役割を調査する.
HIF-1がT細胞サブセットの発達を制御する分子メカニズムを解明する.
T細胞媒介の自己免疫疾患におけるHIF-1のインビヴォ関連性を評価する.

主な方法:

異なる酸素条件下でのT細胞の微分化の分析.
転写活性化,タンパク質複合体形成,およびプロテアソモール分解を含む分子研究.
実験的な自己免疫性脳炎 (EAE) をモデル化するために,遺伝子組み換えマウス (HIF-1α欠乏性T細胞) を用いたインビボ試験.

主要な成果:

HIF-1は,RORγtを活性化し,IL-17プロモーターにコアクティベーターの勧誘を容易にすることによって,T(H) 17の分化を促進します.
HIF-1は,Foxp3と結合し,その分解を促すことでT (((reg) の発育を阻害する.
HIF-1α欠乏性T細胞は,減少したT (H) 17と増加したT (reg) 集団を示し,EAEに対する耐性を授与する.
HIF-1のこれらの調節効果は,ノルモキシカル条件とヒポキシカル条件の両方で観察されます.

結論:

HIF-1は,T細胞系統のコミットメントを決定する重要な代謝センサーとして機能します.
特にHIF-1を標的とした代謝調節は,T細胞集団のバランスを取り戻し,T細胞媒介の自己免疫病理を治療する可能性がある.
これらの発見は,適応性免疫反応の形成における代謝シグナルの重要性を強調しています.

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