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KIR3DL1 Allotype-Dependent Modulation of NK Cell Immunity against Chronic Myeloid Leukemia

Izumi, Kiyotaka 京都大学 DOI:10.14989/doctor.k23775

2022.03.23

概要

【背景】
チロシンキナーゼ阻害剤（TKI）の投与を受けた慢性骨髄性白血病（CML）患者のうちNK 細胞の増加を伴う症例は良好な予後を示す (Lancet Hematol 2015; 2: e528, Leukemia 2017;35: 298)。NK 細胞の機能は細胞表面に発現する種々の受容体により調節されるが、中でも killercell immunoglobulin-like receptor （KIR）は、複数のサブタイプと豊富なアレル多型を有している。その一つKIR3DL1はNK細胞を抑制する受容体で、HLA-Bを主なリガンドとする。KIR3DL1とHLA-B の会合親和性は両アレルの組み合わせで強・弱・なしの3 段階に分類され、親和性が高いほど NK 細胞を強く抑制する。KIR3DL1 アレル多型が CML における TKI の効果と相関するとされ(Cancer Immunol Res 2018; 6: 745)、CML におけるKIR3DL1 の重要性が示唆された。そこで本研究では CML に対する NK 細胞免疫が KIR3DL1 アレル多型によりどう調節されるかを解析した。

【方法】
CML 由来細胞株K562 をヒトNK 細胞と共培養し、NK 細胞のCD107a 脱顆粒と細胞傷害活性をフローサイトメトリーで測定した。標的としてK562 に加えて複数のHLA アレルを導入したK562、TKI 耐性遺伝子T315I 変異を導入したK562（T315I 株）およびHLA 導入T315I 株を使用した。NK 細胞として健常人と CML 患者末梢血由来の単核球、さらに NK 細胞株 NK-92とKIR3DL1 導入NK-92 を用いた。

【結果】
末梢血 NK 細胞における KIR3DL1 蛋白の発現レベルは KIR3DL1 アレルで規定され、低発現(3DL1-low: *007)と高発現(3DL1-high:*01502、*001)とに分類された。KIR3DL1 陽性NK細胞の CD107a 脱顆粒は KIR3DL1 発現レベルと HLA-B の組み合わせに基づいて調節された。すなわち3DL1-low NK 細胞のCD107a 脱顆粒はB*44:03 導入株との共培養でK562 親株と同等の活性を示したが、B*52:01 導入株との共培養では抑制された。一方3DL1-high NK 細胞の活性は両者でともに抑制された。また抗 KIR3DL1 抗体 Z27 の添加でこれらの抑制はいずれも解除された。TKI の 1 つ dasatinib に NK 細胞を暴露すると、KIR3DL1 と HLA-B の会合親和性が弱いもしくはない場合に、NK 細胞活性が増強した。T315I 変異を有する K562 株に対してもdasatinib はNK 細胞の細胞傷害性を増強した。NK-92 細胞にKIR3DL1*01502 アレルを導入すると細胞表面にKIR3DL1 蛋白が発現し、その細胞傷害活性は標的細胞に発現するHLA-B に依存して抑制された。ここでもZ27 の添加で、HLA-B によるNK-92 への抑制が解除された。さらにCML 患者のNK 細胞でも、健常人由来NK 細胞と同様にKIR3DL1 の発現レベルによってHLAB による抑制度合いが規定された。

【結論】
KIR3DL1 とHLA-B アレルの組み合わせがdasatinib によるNK 細胞活性化を調節することが示された。本研究は CML に対する NK 細胞免疫において KIR3DL1 が重要な役割を担うことを裏付けるとともに、アレル多型に基づいたKIR3DL1 シグナルの阻害が、CML に対する新規免疫チェックポイント阻害療法となる可能性を示すものである。

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