Cotton Rachel N, Wegrecki Marcin, Cheng Tan-Yun, Chen Yi-Ling, Veerapen Natacha, Le Nours Jérôme, Orgill Dennis P, Pomahac Bohdan, Talbot Simon G, Willis Richard, Altman John D, de Jong Annemieke, Van Rhijn Ildiko, Clark Rachael A, Besra Gurdyal S, Ogg Graham, Rossjohn Jamie, Moody D Branch
Graduate Program in Immunology, Harvard Medical School, Boston, MA.
Division of Rheumatology, Inflammation and Immunity, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
J Exp Med. 2021 Jul 5;218(7). doi: 10.1084/jem.20202699. Epub 2021 May 7.
We optimized lipidomics methods to broadly detect endogenous lipids bound to cellular CD1a proteins. Whereas membrane phospholipids dominate in cells, CD1a preferentially captured sphingolipids, especially a C42, doubly unsaturated sphingomyelin (42:2 SM). The natural 42:2 SM but not the more common 34:1 SM blocked CD1a tetramer binding to T cells in all human subjects tested. Thus, cellular CD1a selectively captures a particular endogenous lipid that broadly blocks its binding to TCRs. Crystal structures show that the short cellular SMs stabilized a triad of surface residues to remain flush with CD1a, but the longer lipids forced the phosphocholine group to ride above the display platform to hinder TCR approach. Whereas nearly all models emphasize antigen-mediated T cell activation, we propose that the CD1a system has intrinsic autoreactivity and is negatively regulated by natural endogenous inhibitors selectively bound in its cleft. Further, the detailed chemical structures of natural blockers could guide future design of therapeutic blockers of CD1a response.
我们优化了脂质组学方法，以广泛检测与细胞CD1a蛋白结合的内源性脂质。虽然膜磷脂在细胞中占主导地位，但CD1a优先捕获鞘脂，尤其是一种C42、双不饱和鞘磷脂（42:2 SM）。在所有测试的人类受试者中，天然的42:2 SM而非更常见的34:1 SM阻断了CD1a四聚体与T细胞的结合。因此，细胞CD1a选择性捕获一种特定的内源性脂质，该脂质广泛阻断其与TCR的结合。晶体结构表明，短链细胞SMs稳定了一组表面残基，使其与CD1a保持齐平，但较长的脂质迫使磷酸胆碱基团高于展示平台，从而阻碍TCR接近。虽然几乎所有模型都强调抗原介导的T细胞激活，但我们提出CD1a系统具有内在的自身反应性，并受到选择性结合在其裂隙中的天然内源性抑制剂的负调控。此外，天然阻滞剂的详细化学结构可以指导未来CD1a反应治疗性阻滞剂的设计。
