Department of Neurology and Immunobiology, Yale School of Medicine, New Haven, CT 06520.
J Immunol. 2013 Oct 1;191(7):3673-80. doi: 10.4049/jimmunol.1300945. Epub 2013 Aug 26.
CD226 costimulatory signals strongly promote Th1 differentiation, enhancing IFN-γ production by naive T cells. We recently reported that knockdown of CD226 on human T cells resulted in a decrease in T-bet and IFN-γ expression. However, the role of CD226 on Th2 and Th17 cells remains unknown. In this study, we found that CD226 and its ligand CD155 were decreased on Th2-polarized naive T cells, whereas both were highly expressed under Th17 conditions. Most IFN-γ- and IL-17-producing cells expressed high levels of CD226, but production of IL-13 did not correlate with CD226 expression. CD226 knockdown by lentiviral transduction resulted in increased STAT-6 phosphorylation, enhanced GATA3 expression, and consequently higher production of IL-4 and IL-13. Under Th17 conditions, CD226-depleted cells showed slightly impaired IL-17 secretion, suggesting that CD226 contributes, in part, to IL-17 production but is dispensable for Th17 cell generation. In line with these results, CD226 blockade with neutralizing Abs efficiently inhibited T cell activation and proliferation and production of IFN-γ and IL-17, whereas IL-13 secretion remained functional. Taken together, our results establish an important role for CD226 in differentially regulating the proinflammatory (Th1/Th17)/anti-inflammatory (Th2) balance, suggesting that the CD226/CD155 interaction could potentially be targeted in therapeutic approaches to human autoimmune diseases.
CD226 共刺激信号强烈促进 Th1 分化，增强幼稚 T 细胞 IFN-γ 的产生。我们最近报道，敲低人 T 细胞上的 CD226 会导致 T-bet 和 IFN-γ 的表达减少。然而，CD226 在 Th2 和 Th17 细胞上的作用尚不清楚。在这项研究中，我们发现 CD226 及其配体 CD155 在 Th2 极化的幼稚 T 细胞上减少，而在 Th17 条件下两者均高表达。大多数 IFN-γ 和 IL-17 产生细胞表达高水平的 CD226，但 IL-13 的产生与 CD226 表达无关。通过慢病毒转导敲低 CD226 导致 STAT-6 磷酸化增加，GATA3 表达增强，进而导致更高水平的 IL-4 和 IL-13 产生。在 Th17 条件下，CD226 耗尽的细胞显示出轻微受损的 IL-17 分泌，表明 CD226 部分有助于 IL-17 的产生，但对于 Th17 细胞的产生不是必需的。与这些结果一致，用中和抗体阻断 CD226 有效地抑制了 T 细胞的激活、增殖以及 IFN-γ 和 IL-17 的产生，而 IL-13 的分泌仍然具有功能。总之，我们的结果确立了 CD226 在差异调节促炎（Th1/Th17）/抗炎（Th2）平衡中的重要作用，表明 CD226/CD155 相互作用可能成为治疗人类自身免疫性疾病的潜在靶点。
