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 ORCID: https://orcid.org/0000-0002-2020-7522 and Van Rhijn, Ildiko 2019. A T-cell receptor escape channel allows broad T-cell response to CD1b and membrane phospholipids. Nature Communications 10 (1) , -. 10.1038/s41467-018-07898-0

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	Nature Publishing Group
ISSN:	2041-1723
Date of First Compliant Deposit:	10 January 2019
Date of Acceptance:	3 December 2018
Last Modified:	04 May 2023 23:41
URI:	https://orca.cardiff.ac.uk/id/eprint/118287

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