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 () and Ildiko Van Rhijn ()
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Adam Shahine: Monash University
Peter Reinink: Utrecht University
Josephine F. Reijneveld: Utrecht University
Stephanie Gras: Monash University
Mira Holzheimer: University of Groningen
Tan-Yun Cheng: Immunology and Allergy and Harvard Medical School
Adriaan J. Minnaard: University of Groningen
John D. Altman: Emory University School of Medicine
Steffi Lenz: Utrecht University
Jacques Prandi: Université Paul Sabatier
Joanna Kubler-Kielb: National Institutes of Health
D. Branch Moody: Immunology and Allergy and Harvard Medical School
Jamie Rossjohn: Monash University
Ildiko Van Rhijn: Utrecht University

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-018-07898-0

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