Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
J Immunol. 2010 Nov 15;185(10):6031-40. doi: 10.4049/jimmunol.1000176. Epub 2010 Oct 15.
Increasing evidence shows that NK cells regulate adaptive immunity, but the underlying mechanisms are not well understood. In this study, we show that activated human NK cells suppress autologous naive CD4 T cell proliferation in response to allogeneic dendritic cells (DCs) by selectively killing Ag-activated T cells. Naive CD4 T cells, which were initially resistant to NK cell-mediated cytotoxicity, became substantially susceptible to NK cells within a day after priming with DCs. Ag-activated T cells showed various degrees of susceptibility to NK cells. After 1 d of priming with LPS-matured DCs, T cells were less susceptible to NK cells than were T cells primed with TNF-α-matured DCs. Subsequently at day 3, Ag-activated T cells regained resistance to NK cells. The level of HLA-E expression on Ag-activated T cells was closely correlated with resistance to NK cells. HLA-E was highly expressed at day 1 by T cells primed with LPS-matured DCs but not by T cells primed with TNF-α-matured DCs. An Ab blockade revealed a critical role for the HLA-E-NKG2A interaction in the protection of Ag-activated T cells from NK cells. Collectively, this study demonstrates that NK cells impact adaptive immunity through the finely controlled kinetics of HLA-E expression on T cells. Thus, HLA-E may be a new target for immunoregulation.
越来越多的证据表明 NK 细胞调节适应性免疫，但潜在的机制尚不清楚。在这项研究中，我们表明，活化的人 NK 细胞通过选择性杀伤 Ag 激活的 T 细胞来抑制自身幼稚 CD4 T 细胞对同种异体树突状细胞 (DC) 的增殖反应。幼稚 CD4 T 细胞最初对 NK 细胞介导的细胞毒性具有抗性，但在与 DC 孵育一天后，对 NK 细胞变得高度敏感。Ag 激活的 T 细胞对 NK 细胞的敏感性程度不同。在 LPS 成熟的 DC 孵育 1 天后，T 细胞比 TNF-α 成熟的 DC 孵育的 T 细胞对 NK 细胞的敏感性降低。随后在第 3 天，Ag 激活的 T 细胞恢复对 NK 细胞的抗性。Ag 激活的 T 细胞上 HLA-E 的表达水平与对 NK 细胞的抗性密切相关。在 LPS 成熟的 DC 孵育的 T 细胞上，HLA-E 在第 1 天高度表达，但在 TNF-α 成熟的 DC 孵育的 T 细胞上不表达。抗体阻断揭示了 HLA-E-NKG2A 相互作用在保护 Ag 激活的 T 细胞免受 NK 细胞攻击中的关键作用。总之，这项研究表明，NK 细胞通过 T 细胞上 HLA-E 表达的精细控制动力学来影响适应性免疫。因此，HLA-E 可能是免疫调节的新靶点。
