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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 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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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: 19 Oct 2019 02:38

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