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

Research output: Contribution to journalArticleResearchpeer-review

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.

LanguageEnglish
Article number56
Number of pages12
JournalNature Communications
Volume10
Issue number1
DOIs
Publication statusPublished - 4 Jan 2019

Keywords

  • immune tolerance
  • immunology
  • structural biology
  • T-cell receptor

Cite this

Shahine, Adam ; Reinink, Peter ; Reijneveld, Josephine F. ; Gras, Stephanie ; Holzheimer, Mira ; Cheng, Tan Yun ; Minnaard, Adriaan J. ; Altman, John D. ; Lenz, Steffi ; Prandi, Jacques ; Kubler-Kielb, Joanna ; Moody, D. Branch ; Rossjohn, Jamie ; Van Rhijn, Ildiko. / A T-cell receptor escape channel allows broad T-cell response to CD1b and membrane phospholipids. In: Nature Communications. 2019 ; Vol. 10, No. 1.
@article{40ad1a301b5c438d82e77d7432cdc7af,
title = "A T-cell receptor escape channel allows broad T-cell response to CD1b and membrane phospholipids",
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.",
keywords = "immune tolerance, immunology, structural biology, T-cell receptor",
author = "Adam Shahine and Peter Reinink and Reijneveld, {Josephine F.} and Stephanie Gras and Mira Holzheimer and Cheng, {Tan Yun} and Minnaard, {Adriaan J.} and Altman, {John D.} and Steffi Lenz and Jacques Prandi and Joanna Kubler-Kielb and Moody, {D. Branch} and Jamie Rossjohn and {Van Rhijn}, Ildiko",
year = "2019",
month = "1",
day = "4",
doi = "10.1038/s41467-018-07898-0",
language = "English",
volume = "10",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",

}

Shahine, A, Reinink, P, Reijneveld, JF, Gras, S, Holzheimer, M, Cheng, TY, Minnaard, AJ, Altman, JD, Lenz, S, Prandi, J, Kubler-Kielb, J, Moody, DB, Rossjohn, J & Van Rhijn, I 2019, 'A T-cell receptor escape channel allows broad T-cell response to CD1b and membrane phospholipids' Nature Communications, vol. 10, no. 1, 56. https://doi.org/10.1038/s41467-018-07898-0

A T-cell receptor escape channel allows broad T-cell response to CD1b and membrane phospholipids. / Shahine, Adam; Reinink, Peter; Reijneveld, Josephine F.; Gras, Stephanie; Holzheimer, Mira; Cheng, Tan Yun; Minnaard, Adriaan J.; Altman, John D.; Lenz, Steffi; Prandi, Jacques; Kubler-Kielb, Joanna; Moody, D. Branch; Rossjohn, Jamie; Van Rhijn, Ildiko.

In: Nature Communications, Vol. 10, No. 1, 56, 04.01.2019.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - A T-cell receptor escape channel allows broad T-cell response to CD1b and membrane phospholipids

AU - Shahine, Adam

AU - Reinink, Peter

AU - Reijneveld, Josephine F.

AU - Gras, Stephanie

AU - Holzheimer, Mira

AU - Cheng, Tan Yun

AU - Minnaard, Adriaan J.

AU - Altman, John D.

AU - Lenz, Steffi

AU - Prandi, Jacques

AU - Kubler-Kielb, Joanna

AU - Moody, D. Branch

AU - Rossjohn, Jamie

AU - Van Rhijn, Ildiko

PY - 2019/1/4

Y1 - 2019/1/4

N2 - 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.

AB - 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.

KW - immune tolerance

KW - immunology

KW - structural biology

KW - T-cell receptor

UR - http://www.scopus.com/inward/record.url?scp=85059503511&partnerID=8YFLogxK

U2 - 10.1038/s41467-018-07898-0

DO - 10.1038/s41467-018-07898-0

M3 - Article

VL - 10

JO - Nature Communications

T2 - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 56

ER -