Le Dréan E, Vély F, Olcese L, Cambiaggi A, Guia S, Krystal G, Gervois N, Moretta A, Jotereau F, Vivier E
INSERM U463, Institut de Biologie et Faculté des Sciences, Nantes, France.
Eur J Immunol. 1998 Jan;28(1):264-76. doi: 10.1002/(SICI)1521-4141(199801)28:01<264::AID-IMMU264>3.0.CO;2-O.
Subsets of T and natural killer (NK) lymphocytes express the CD94-NKG2A heterodimer, a receptor for major histocompatibility complex class I molecules. We show here that engagement of the CD94-NKG2A heterodimer inhibits both antigen-driven tumor necrosis factor (TNF) release and cytotoxicity on melanoma-specific human T cell clones. Similarly, CD16-mediated NK cell cytotoxicity is extinguished by cross-linking of the CD94-NKG2A heterodimer. Combining in vivo and in vitro analysis, we report that both I/VxYxxL immunoreceptor tyrosine-based inhibition motifs (ITIM) present in the NKG2A intracytoplasmic domain associate upon tyrosine phosphorylation with the protein tyrosine phosphatases SHP-1 and SHP-2, but not with the polyinositol phosphatase SHIP Determination of the dissociation constant, using surface plasmon resonance analysis, indicates that NKG2A phospho-ITIM interact directly with the SH2 domains of SHP-1 and SHP-2 with a high affinity. Engagement of the CD94-NKG2A heterodimer therefore appears as a protein-tyrosine phosphatase-based strategy that negatively regulates both antigen-induced T cell response and antibody-induced NK cell cytotoxicity. Our results suggest that this inhibitory pathway sets the threshold of T and NK cell activation.
T淋巴细胞和自然杀伤（NK）淋巴细胞的亚群表达CD94-NKG2A异二聚体，这是一种主要组织相容性复合体I类分子的受体。我们在此表明，CD94-NKG2A异二聚体的激活会抑制抗原驱动的肿瘤坏死因子（TNF）释放以及对黑色素瘤特异性人类T细胞克隆的细胞毒性。同样，CD94-NKG2A异二聚体的交联会消除CD16介导的NK细胞细胞毒性。结合体内和体外分析，我们报告NKG2A胞质结构域中存在的两个I/VxYxxL免疫受体酪氨酸抑制基序（ITIM）在酪氨酸磷酸化后与蛋白酪氨酸磷酸酶SHP-1和SHP-2结合，但不与多肌醇磷酸酶SHIP结合。使用表面等离子体共振分析测定解离常数表明，NKG2A磷酸化ITIM与SHP-1和SHP-2的SH2结构域直接高亲和力相互作用。因此，CD94-NKG2A异二聚体的激活似乎是一种基于蛋白酪氨酸磷酸酶的策略，可负向调节抗原诱导的T细胞反应和抗体诱导的NK细胞细胞毒性。我们的结果表明，这种抑制途径设定了T细胞和NK细胞激活的阈值。
