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マウス表皮T細胞の発生における胎生期および新生仔期T細胞受容体シグナルの役割

須藤, 恒一 京都大学 DOI:10.14989/doctor.k24118

2022.05.23

概要

Vγ5Vδ1 T 細胞受容体(TCR)を発現するγδT 細胞(Vγ5Vδ1+T 細胞)は胎生期の胸腺でのみ発生し、表皮へ移動した後は樹状突起を持ったdendritic epidermal T cell(DETC)として増殖を繰り返し、感染防御や発がん抑制など皮膚恒常性の維持に働いている。これまで、 TCR 関連分子の遺伝子欠損マウスを用いた研究から、Vγ5Vδ1+T 細胞の発生には TCR シグナルが重要である事が示唆されてきた。例えば、TCR シグナル伝達分子である ZAP70 および Syk を個々に欠損したマウスでは、DETC の細胞数が減少するが、これらのマウスの胎生期胸腺では Vγ5Vδ1+T 細胞の細胞数は変化しなかった。一方で、ZAP70 と Syk の二重欠損マウスでは胸腺においては Vγ5Vδ1+T 細胞が減少した。これらの結果より、TCR シグナルが Vγ5Vδ1+T 細胞/DETC の発生・分化に関与することは確かである。しかし、TCR シグナルの強度が、どのように Vγ5Vδ1+T 細胞/DETC の発生・分化に影響するかは十分に明らかになっていない。この点を詳細に検証するためには、従来のような遺伝子欠失マウスの使用には限界があると考えた。そこで、本研究では、ZAP70 に点突然変異を持ち TCR シグナルが部分的に減弱した SKG マウスを用いて、Vγ5Vδ1+T 細胞の発生におけるTCR シグナルの役割を検証した。

成体 SKG マウスの表皮では DETC の細胞数が WT マウスの約 10%にまで低下しており、樹状突起の減少を示した。一方で、胎生期胸腺では Vγ5Vδ1+T 細胞の細胞数はWT マウスの約 50%程度までにしか低下していなかった。また、SKG 変異により Vγ5Vδ1+T 細胞は増殖細胞の割合と IL-15 経路への応答性が低下していた。一方で、Vγ5Vδ1+T 細胞の胎生期胸腺内の局在性と Syk の発現量、およびサイトカイン産生能力は WT マウスとSKG マウスで差は見られなかった。

次に生後早期の表皮を調べた結果、SKG マウスにおいて DETC の細胞数は WT マウスの約 50%程度であった。しかし、経時的な細胞数および形態の変化を検証したところ、WT マウスでは DETC の細胞数の増加と樹状突起の形成を観察したのに対して、SKG マウスではそのどちらも観察できなかった。さらに WT マウスと SKG マウスの F1 マウスの胎生期胸腺では Vγ5Vδ1+T 細胞の細胞数は WT マウスと同程度だったのに対して、成体表皮では DETC の細胞数はSKG マウスと同等に減少していた。さらに、無菌マウス(Germ-free マウス)と SPF マウス間で DETC の細胞数および形態に差は見られなかったことから、表皮における DETC の分化・増殖は皮膚細菌叢非依存的に行われると考えられた。

以上の結果から、Vγ5Vδ1TCR シグナルはそれぞれ胸腺と表皮における Vγ5Vδ1+T 細胞と DETC の発生・分化段階において共に重要であるが、その必要な強度はそれぞれの段階で異なることが示唆された。

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