A molecular basis of human T cell receptor autoreactivity toward self-phospholipids

Adam Shahine, Ildiko Van Rhijn, Tan-Yun Cheng, Sarah Iwany, Stephanie Gras, D Branch Moody, Jamie Rossjohn

Research output: Contribution to journalArticleResearchpeer-review

15 Citations (Scopus)

Abstract

Human T cell autoreactivity toward lipid antigens presented by CD1 proteins can manifest in numerous diseases, in- cluding psoriasis, contact hypersensitivities, and allergies. However, the molecular mechanisms for regulating T cell autoreactivity toward lipid antigens remain unclear. We determined the basis for T cell receptor (TCR) autoreactivity toward CD1b bound to self-phospholipids. The spectrum of self-antigens captured by CD1b skews toward abundant membrane phospholipids such as phosphatidylcholine and phosphatidylethanolamine. However, TCRs can specifically recognize rare phospholipids including phosphatidylglycerol (PG). The structure of an autoreactive TCR bound to CD1b-PG shows that discrimination occurs through a marked induced fit movement of PG so that its polar head group fits snugly into the cationic cup of the TCR. Conversely, TCR binding toward ubiquitous self-phospholipids was sterically or electrostatically repelled. Accordingly, we describe a mechanism of TCR autoreactivity toward rare phospholipids and avoidance of autoreactivity to the most abundant self-phospholipids.
Original languageEnglish
Number of pages12
JournalScience Immunology
Volume2
DOIs
Publication statusPublished - 20 Oct 2017

Keywords

  • Autoimmunity
  • X-ray crystallography

Cite this

@article{f6b49e56a67d40c2a6f6a339640b4d89,
title = "A molecular basis of human T cell receptor autoreactivity toward self-phospholipids",
abstract = "Human T cell autoreactivity toward lipid antigens presented by CD1 proteins can manifest in numerous diseases, in- cluding psoriasis, contact hypersensitivities, and allergies. However, the molecular mechanisms for regulating T cell autoreactivity toward lipid antigens remain unclear. We determined the basis for T cell receptor (TCR) autoreactivity toward CD1b bound to self-phospholipids. The spectrum of self-antigens captured by CD1b skews toward abundant membrane phospholipids such as phosphatidylcholine and phosphatidylethanolamine. However, TCRs can specifically recognize rare phospholipids including phosphatidylglycerol (PG). The structure of an autoreactive TCR bound to CD1b-PG shows that discrimination occurs through a marked induced fit movement of PG so that its polar head group fits snugly into the cationic cup of the TCR. Conversely, TCR binding toward ubiquitous self-phospholipids was sterically or electrostatically repelled. Accordingly, we describe a mechanism of TCR autoreactivity toward rare phospholipids and avoidance of autoreactivity to the most abundant self-phospholipids.",
keywords = "Autoimmunity, X-ray crystallography",
author = "Adam Shahine and {Van Rhijn}, Ildiko and Tan-Yun Cheng and Sarah Iwany and Stephanie Gras and Moody, {D Branch} and Jamie Rossjohn",
year = "2017",
month = "10",
day = "20",
doi = "10.1126/sciimmunol.aao1384",
language = "English",
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journal = "Science Immunology",
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A molecular basis of human T cell receptor autoreactivity toward self-phospholipids. / Shahine, Adam; Van Rhijn, Ildiko; Cheng, Tan-Yun; Iwany, Sarah; Gras, Stephanie; Moody, D Branch; Rossjohn, Jamie.

In: Science Immunology, Vol. 2, 20.10.2017.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - A molecular basis of human T cell receptor autoreactivity toward self-phospholipids

AU - Shahine, Adam

AU - Van Rhijn, Ildiko

AU - Cheng, Tan-Yun

AU - Iwany, Sarah

AU - Gras, Stephanie

AU - Moody, D Branch

AU - Rossjohn, Jamie

PY - 2017/10/20

Y1 - 2017/10/20

N2 - Human T cell autoreactivity toward lipid antigens presented by CD1 proteins can manifest in numerous diseases, in- cluding psoriasis, contact hypersensitivities, and allergies. However, the molecular mechanisms for regulating T cell autoreactivity toward lipid antigens remain unclear. We determined the basis for T cell receptor (TCR) autoreactivity toward CD1b bound to self-phospholipids. The spectrum of self-antigens captured by CD1b skews toward abundant membrane phospholipids such as phosphatidylcholine and phosphatidylethanolamine. However, TCRs can specifically recognize rare phospholipids including phosphatidylglycerol (PG). The structure of an autoreactive TCR bound to CD1b-PG shows that discrimination occurs through a marked induced fit movement of PG so that its polar head group fits snugly into the cationic cup of the TCR. Conversely, TCR binding toward ubiquitous self-phospholipids was sterically or electrostatically repelled. Accordingly, we describe a mechanism of TCR autoreactivity toward rare phospholipids and avoidance of autoreactivity to the most abundant self-phospholipids.

AB - Human T cell autoreactivity toward lipid antigens presented by CD1 proteins can manifest in numerous diseases, in- cluding psoriasis, contact hypersensitivities, and allergies. However, the molecular mechanisms for regulating T cell autoreactivity toward lipid antigens remain unclear. We determined the basis for T cell receptor (TCR) autoreactivity toward CD1b bound to self-phospholipids. The spectrum of self-antigens captured by CD1b skews toward abundant membrane phospholipids such as phosphatidylcholine and phosphatidylethanolamine. However, TCRs can specifically recognize rare phospholipids including phosphatidylglycerol (PG). The structure of an autoreactive TCR bound to CD1b-PG shows that discrimination occurs through a marked induced fit movement of PG so that its polar head group fits snugly into the cationic cup of the TCR. Conversely, TCR binding toward ubiquitous self-phospholipids was sterically or electrostatically repelled. Accordingly, we describe a mechanism of TCR autoreactivity toward rare phospholipids and avoidance of autoreactivity to the most abundant self-phospholipids.

KW - Autoimmunity

KW - X-ray crystallography

U2 - 10.1126/sciimmunol.aao1384

DO - 10.1126/sciimmunol.aao1384

M3 - Article

VL - 2

JO - Science Immunology

JF - Science Immunology

SN - 2470-9468

ER -