メタボリートBH4は,自己免疫およびがんにおけるT細胞増殖を制御する

Shane J F Cronin^1,2,3, Corey Seehus^2,3, Adelheid Weidinger⁴

¹IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria.

Nature

|November 9, 2018

まとめ

テトラヒドロビオプテリン (BH4) はT細胞の増殖と機能に不可欠です. BH4のレベルを操作することで,自己免疫疾患を阻害し,抗がん免疫力を高めることができます.

科学分野:

免疫学
生物化学
細胞生物学

背景:

テトラヒドロビオプテリン (BH4) は,神経伝達物質の合成と窒素酸化物の生成に不可欠なコファクターである.
T細胞の活性化は免疫反応,自己免疫,がんにおいて極めて重要です.
T細胞の生物学におけるBH4の役割は以前は未研究であった.

研究の目的:

T細胞の生物学における BH4 の役割を調査する.
BH4合成経路を標的として免疫反応を調節できるかどうかを判断する.

主な方法:

T細胞におけるGTPサイクロヒドローラゼ1 (GCH1) の遺伝的不活性化とセピアプテリン還元酵素 (SPR) の抑制.
T細胞の増殖,鉄代謝,ミトコンドリアのバイオエナジェティクスの評価
自己免疫,アレルギー性炎症,がんのマウスモデルを用いた in vivo 研究.
BH4およびSPR抗剤の投与

主要な成果:

BH4合成は成熟したマウスとヒトのT細胞増殖に不可欠です.
T細胞のBH4生成は,鉄代謝とミトコンドリア機能の変化と相関しています.
BH4の合成を阻害すると,T細胞媒介の自己免疫とアレルギー性炎症を無効化する.
BH4レベルを高めると,CD4+とCD8+T細胞の抗腫瘍活性が増加する.
BH4の投与は腫瘍の増殖を抑制し,腫瘍内エフェクターT細胞を増やす.
キヌレニンのT細胞増殖抑制は,BH4によって救出することができます.

結論:

BH4はT細胞生物学の基本的レギュラーです.
GCH1,SPR,BH4はT細胞の反応を調節する重要な標的である.
BH4経路の操作は自身免疫疾患や癌の治療の可能性を提供しています

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