Laboratory of Immunomedicine, Department of Immunology & O2, School of Medicine, Complutense University of Madrid, Madrid, Spain.
Front Immunol. 2022 Jan 19;12:740613. doi: 10.3389/fimmu.2021.740613. eCollection 2021.
The oral mucosa is constantly exposed to a plethora of stimuli including food antigens, commensal microbiota and pathogens, requiring distinct immune responses. We previously reported that human oral epithelial cells (OECs) suppress immune responses to bacteria, using H413 and TR146 OEC lines and primary OECs in co-culture with dendritic cells (DCs) and T cells (OEC-conditioned cells). OECs reduced DCs expression of CD80/CD86 and IL-12/TNFα release and impaired T cell activation. Here, we further evaluated the immunosuppression by these OECs and investigated the underlying mechanisms. OEC-conditioned DCs did not induce CD4 T cell polarization towards Treg, judging by the absence of FoxP3 expression. OECs also repressed T-bet/IFNγ expression in CD4 and CD8 T cells activated by DCs or anti-CD3/CD28 antibodies. This inhibition depended on OEC:T cell ratio and IFNγ repression occurred at the transcriptional level. Time-lapse experiments showed that OECs inhibited early steps of T cell activation, consistent with OECs inability to suppress T cells stimulated with PMA/ionomycin. Blocking CD40/CD40L, CD58/CD2 and PD-L1/PD-1 interactions with specific antibodies did not disrupt T cell suppression by OECs. However, preventing prostaglandin E2 (PGE2) synthesis or blocking PGE2 binding to the cognate EP2/EP4 receptors, restored IFNγ and TNFα production in OEC-conditioned T cells. Finally, treating OECs with poly(I:C), which simulates viral infections, limited T cell suppression. Overall, these results point to an inherent ability of OECs to suppress immune responses, which can nonetheless be eluded when OECs are under direct assault.
口腔黏膜不断受到各种刺激的影响，包括食物抗原、共生菌群和病原体，这需要独特的免疫反应。我们之前报道过，人类口腔上皮细胞（OECs）通过 H413 和 TR146 OEC 系以及与树突状细胞（DCs）和 T 细胞（OEC 条件细胞）共培养的原代 OEC 抑制对细菌的免疫反应。OECs 降低了 DCs 表达 CD80/CD86 和 IL-12/TNFα 的释放，并损害了 T 细胞的激活。在这里，我们进一步评估了这些 OEC 的免疫抑制作用，并研究了潜在的机制。通过缺乏 FoxP3 表达，我们判断 OEC 条件化的 DC 不会诱导 CD4 T 细胞向 Treg 极化。OECs 还抑制了由 DC 或抗 CD3/CD28 抗体激活的 CD4 和 CD8 T 细胞中 T-bet/IFNγ 的表达。这种抑制依赖于 OEC：T 细胞的比例，并且 IFNγ 的抑制发生在转录水平。延时实验表明，OEC 抑制 T 细胞激活的早期步骤，这与 OEC 无法抑制 PMA/离子霉素刺激的 T 细胞一致。用特异性抗体阻断 CD40/CD40L、CD58/CD2 和 PD-L1/PD-1 相互作用并不能破坏 OEC 对 T 细胞的抑制作用。然而，阻止前列腺素 E2 (PGE2) 的合成或阻断 PGE2 与同源 EP2/EP4 受体结合，恢复了 OEC 条件化 T 细胞中 IFNγ 和 TNFα 的产生。最后，用 poly(I:C) 处理 OEC，模拟病毒感染，限制了 T 细胞的抑制作用。总的来说，这些结果表明 OEC 具有固有抑制免疫反应的能力，但当 OEC 受到直接攻击时，这种能力可能会被规避。
