Table_1_MAIT Cells Display a Specific Response to Type 1 IFN Underlying the Adjuvant Effect of TLR7/8 Ligands.XLSX

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 in vitro, 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细胞（Mucosal-associated invariant T cells，MAIT）是一类高度保守的效应T细胞（effector T cells）亚群，在人体中可介导类天然识别多种细菌与真菌。靶向调控这类细胞的功能，有望成为对抗难治性细菌感染的新型免疫治疗策略，实现重大突破。然而，尽管目前在MAIT细胞强效激动配体的设计上已取得进展，但越来越多研究表明，需借助佐剂才能诱导该细胞发挥强效抗菌效应功能，例如γ干扰素（IFNγ）的产生与细胞毒性作用。事实上，仅通过T细胞受体（T cell receptor，TCR）触发，MAIT细胞主要产生屏障修复相关功能；而要驱动其抗菌功能，则需要炎性微环境的参与。白细胞介素（Interleukin，IL）-7、IL-12、IL-18、IL-15以及近年发现的I型干扰素（type 1 IFN）等细胞因子，在体外均能与TCR刺激协同，诱导MAIT细胞产生γ干扰素或发挥细胞毒性功能，但其具体作用机制尚未明确。本研究中，我们发现MAIT细胞具备响应α干扰素（IFNα）的内在机制。我们证实，α干扰素可直接且特异性地作用于MAIT细胞，并与TCR/CD3触发协同，以最大化诱导细胞因子产生与细胞毒性功能。我们的研究证据表明，信号转导与转录激活因子4（Signal transducer and activator of transcription 4，Stat4）通路的优先激活，参与了MAIT细胞对α干扰素刺激的高敏感性。最后，基因表达数据证实了MAIT细胞对α干扰素的特异性响应，并明确了该细胞因子可能作用的特定通路。综上，本研究数据表明，诱导α干扰素产生的佐剂，有望通过最大化MAIT细胞对纯化配体的响应能力，从而诱导强效抗感染免疫应答。