Cameron Garth, Nguyen Tram, Ciula Marcin, Williams Spencer J, Godfrey Dale I
Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne Melbourne VIC 3000 Australia
School of Chemistry, University of Melbourne Parkville VIC 3010 Australia
Chem Sci. 2023 May 27;14(29):7887-7896. doi: 10.1039/d3sc02124f. eCollection 2023 Jul 26.
Natural Killer T (NKT) cells are a lipid-antigen reactive T cell subset that is restricted to the antigen presenting molecule CD1d. They possess diverse functional properties that contribute to inflammatory and regulatory immune responses. The most studied lipid antigen target for these T cells is α-galactosylceramide (αGC). The commensal organism () produces several forms of αGC, but conflicting information exists about the influence of these lipids on NKT cells. Herein, we report the total synthesis of a major form of αGC from ( αGC), and several analogues thereof. We confirm the T cell receptor (TCR)-mediated recognition of these glycolipids by mouse and human NKT cells. Despite the natural structure of αGC containing lipid branching that limits potency, we demonstrate that αGC drives mouse NKT cells to proliferate and differentiate into producers of the immunoregulatory cytokine, interleukin-10 (IL-10). These αGC-experienced NKT cells display regulatory function by inhibiting the expansion of naïve NKT cells upon subsequent exposure to this antigen. Moreover, this regulatory activity impacts more than just NKT cells, as demonstrated by the NKT cell-mediated inhibition of antigen-stimulated mucosal-associated invariant T (MAIT) cells (a T cell subset restricted to a different antigen presenting molecule, MR1). These findings reveal that derived NKT cell agonists may have broad immunoregulatory activity, providing insight into the mechanisms influencing immune tolerance to commensal bacteria and highlighting a potential means to manipulate NKT cell function for therapeutic benefit.
自然杀伤T（NKT）细胞是一类脂质抗原反应性T细胞亚群，其受限于抗原呈递分子CD1d。它们具有多种功能特性，有助于炎症性和调节性免疫反应。这些T细胞研究最多的脂质抗原靶点是α-半乳糖神经酰胺（αGC）。共生生物（）产生多种形式的αGC，但关于这些脂质对NKT细胞的影响存在相互矛盾的信息。在此，我们报道了从（αGC）全合成一种主要形式的αGC及其几种类似物。我们证实了小鼠和人类NKT细胞通过T细胞受体（TCR）介导对这些糖脂的识别。尽管αGC的天然结构含有限制效力的脂质分支，但我们证明αGC能驱动小鼠NKT细胞增殖并分化为免疫调节细胞因子白细胞介素-10（IL-10）的产生细胞。这些经历过αGC的NKT细胞在随后接触该抗原时通过抑制幼稚NKT细胞的扩增而发挥调节功能。此外，这种调节活性的影响不止于NKT细胞，如NKT细胞介导的对抗原刺激的黏膜相关恒定T（MAIT）细胞（一种受限于不同抗原呈递分子MR1的T细胞亚群）的抑制所示。这些发现揭示了源自的NKT细胞激动剂可能具有广泛的免疫调节活性，为影响对共生细菌免疫耐受的机制提供了见解，并突出了一种为治疗益处而操纵NKT细胞功能的潜在手段。
