INSERM UMR 1043, Centre de Physiopathologie de Toulouse-Purpan, Toulouse, France.
Paul Sabatier University Toulouse III, Toulouse, France.
Front Immunol. 2020 Sep 8;11:2097. doi: 10.3389/fimmu.2020.02097. eCollection 2020.
Mucosal-associated invariant T (MAIT) cells constitute a highly conserved subset of effector T cells with innate-like recognition of a wide array of bacteria and fungi in humans. Harnessing the potential of these cells could represent a major advance as a new immunotherapy approach to fight difficult-to-treat bacterial infections. However, despite recent advances in the design of potent agonistic ligands for MAIT cells, it has become increasingly evident that adjuvants are required to elicit potent antimicrobial effector functions by these cells, such as IFNγ production and cytotoxicity. Indeed, TCR triggering alone elicits mostly barrier repair functions in MAIT cells, whereas an inflammatory milieu is required to drive the antibacterial functions. Cytokines such as IL-7, IL-12 and IL-18, IL-15 or more recently type 1 IFN all display an apparently similar ability to synergize with TCR stimulation to induce IFNγ production and/or cytotoxic functions , but their mechanisms of action are not well established. Herein, we show that MAIT cells feature a build-in mechanism to respond to IFNα. We confirm that IFNα acts directly and specifically on MAIT cells and synergizes with TCR/CD3 triggering to induce maximum cytokine production and cytotoxic functions. We provide evidences suggesting that the preferential activation of the Stat4 pathway is involved in the high sensitivity of MAIT cells to IFNα stimulation. Finally, gene expression data confirm the specific responsiveness of MAIT cells to IFNα and pinpoints specific pathways that could be the target of this cytokine. Altogether, these data highlight the potential of IFNα-inducing adjuvants to maximize MAIT cells responsiveness to purified ligands in order to induce potent anti-infectious responses.
黏膜相关恒定 T（MAIT）细胞是效应 T 细胞的一个高度保守亚群，具有先天识别多种细菌和真菌的能力。利用这些细胞的潜力可能代表着一种重大进展，因为它们是一种新的免疫治疗方法，可以对抗难以治疗的细菌感染。然而，尽管最近在设计强效 MAIT 细胞激动配体方面取得了进展，但越来越明显的是，需要佐剂来激发这些细胞产生有效的抗菌效应功能，如 IFNγ 的产生和细胞毒性。事实上，TCR 触发本身主要在 MAIT 细胞中引发屏障修复功能，而需要炎症环境来驱动抗菌功能。细胞因子如 IL-7、IL-12 和 IL-18、IL-15 或最近的 I 型 IFN 都表现出类似的协同 TCR 刺激诱导 IFNγ 产生和/或细胞毒性功能的能力，但它们的作用机制尚未得到很好的确立。在此，我们表明 MAIT 细胞具有对 IFNα 作出反应的内置机制。我们证实 IFNα 直接且特异性地作用于 MAIT 细胞，并与 TCR/CD3 触发协同作用，诱导最大的细胞因子产生和细胞毒性功能。我们提供的证据表明，Stat4 途径的优先激活参与了 MAIT 细胞对 IFNα 刺激的高敏感性。最后，基因表达数据证实了 MAIT 细胞对 IFNα 的特异性反应，并确定了可能是该细胞因子靶点的特定途径。总之，这些数据强调了 IFNα 诱导佐剂的潜力，以最大限度地提高 MAIT 细胞对纯化配体的反应性，从而诱导有效的抗感染反应。
