Lipidomic scanning of self- lipids identifies headless antigens for natural killer T cells

• 成果类型: Article
• 署名作者: Cheng, Tan - Yun; Praveena, T.; Govindarajan, Srinath; Almeida, Catarina F.; Pellicci, Daniel G.; Arkins, Wellington C.; Van Rhijn, Ildiko; Venken, Koen; Elewaut, Dirk; Godfrey, Dale I.; Rossjohn, Jamie; Moody, D. Branch
• 署名单位: Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard University; Harvard Medical School; Monash University; Monash University; Flanders Institute for Biotechnology (VIB); Ghent University; Ghent University; University of Melbourne; Peter Doherty Institute; Cardiff University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14647
• DOI: 10.1073/pnas.2321686121
• 发表日期: 2024-08-20
• 关键词: nkt cells; alpha-beta; RECOGNITION; ceramide; receptor; glycolipids; activation; apoptosis; peptide; complex

摘要

To broadly measure the spectrum of cellular self- antigens for natural killer T cells (NKT), we developed a sensitive lipidomics system to analyze lipids trapped between CD1d and NKT T cell receptors (TCRs). We captured diverse antigen complexes formed in cells from natural endogenous lipids, with or without inducing endoplasmic reticulum (ER) stress. After separating protein complexes with no, low, or high CD1d-TCR interaction, we eluted lipids to establish the spectrum of self- lipids that facilitate this interaction. Although this unbiased approach identified fifteen molecules, they clustered into only two related groups: previously known phospholipid antigens and unexpected neutral lipid antigens. Mass spectrometry studies identified the neutral lipids as ceramides, deoxyceramides, and diacylglycerols, which can be considered headless lipids because they lack polar headgroups that usually form the TCR epitope. The crystal structure of the TCR-ceramide-CD1d complex showed how the missing headgroup allowed the TCR to predominantly contact CD1d, supporting a model of CD1d auto- reactivity. Ceramide and related headless antigens mediated physiological TCR binding affinity, weak NKT cell responses, and tetramer binding to polyclonal human and mouse NKT cells. Ceramide and sphingomyelin are oppositely regulated components of the sphingomyelin cycle that are altered during apoptosis, transformation, and ER stress. Thus, the unique molecular link of ceramide to NKT cell response, along with the recent identification of sphingomyelin blockers of NKT cell activation, provide two mutually reinforcing links for NKT cell response to sterile cellular stress conditions.