A T-cell receptor escape channel allows broad T-cell response to CD1b and membrane phospholipids

Adam Shahine, Peter Reinink, Josephine F Reijneveld, Stephanie Gras, Mira Holzheimer, Tan-Yun Cheng, Adriaan J Minnaard, John D Altman, Steffi Lenz, Jacques Prandi, Joanna Kubler-Kielb, D Branch Moody, Jamie Rossjohn*, Ildiko Van Rhijn

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

10 Citations (Scopus)
308 Downloads (Pure)

Abstract

CD1 proteins are expressed on dendritic cells, where they display lipid antigens to T-cell receptors (TCRs). Here we describe T-cell autoreactivity towards ubiquitous human membrane phospholipids presented by CD1b. These T-cells discriminate between two major types of lipids, sphingolipids and phospholipids, but were broadly cross-reactive towards diverse phospholipids including phosphatidylcholine, phosphatidylinositol and phosphatidylethanolamine. The crystal structure of a representative TCR bound to CD1b-phosphatidylcholine provides a molecular mechanism for this promiscuous recognition. We observe a lateral escape channel in the TCR, which shunted phospholipid head groups sideways along the CD1b-TCR interface, without contacting the TCR. Instead the TCR recognition site involved the neck region phosphate that is common to all major self-phospholipids but absent in sphingolipids. Whereas prior studies have focused on foreign lipids or rare self-lipids, we define a new molecular mechanism of promiscuous recognition of common self-phospholipids including those that are known targets in human autoimmune disease.

Original languageEnglish
Article number56
JournalNature Communications
Volume10
Issue number1
DOIs
Publication statusPublished - 4-Jan-2019

Keywords

  • DIACYLATED SULFOGLYCOLIPIDS
  • SELF-GLYCOLIPIDS
  • CYTOPLASMIC TAIL
  • RECOGNITION
  • EXPRESSION
  • ANTIGENS
  • LIPIDS
  • ACTIVATION
  • MOLECULES
  • FAMILY

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