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

Shahine, A., Reinink, P., Reijneveld, J. F., Gras, S., Holzheimer, M., Cheng, T-Y., Minnaard, A. J., Altman, J. D., Lenz, S., Prandi, J., Kubler-Kielb, J., Moody, D. B., Rossjohn, J. & Van Rhijn, I., 4-Jan-2019, In : Nature Communications. 10, 1, p. 56

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)56
JournalNature Communications
Issue number1
Publication statusPublished - 4-Jan-2019

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