CD1a selectively captures endogenous cellular lipids that broadly block T cell response
Cotton, Rachel N; Wegrecki, Marcin; Cheng, Tan-Yun; Chen, Yi-Ling; Veerapen, Natacha; Le Nours, Jérôme; Orgill, Dennis P; Pomahac, Bohdan; Talbot, Simon G; Willis, Richard; Altman, John D; de Jong, Annemieke; Van Rhijn, Ildiko; Clark, Rachael A; Besra, Gurdyal S; Ogg, Graham; Rossjohn, Jamie; Moody, D Branch
(2021) Journal of Experimental Medicine, volume 218, issue 7
(Article)
Abstract
We optimized lipidomics methods to broadly detect endogenous lipids bound to cellular CD1a proteins. Whereas membrane phospholipids dominate in cells, CD1a preferentially captured sphingolipids, especially a C42, doubly unsaturated sphingomyelin (42:2 SM). The natural 42:2 SM but not the more common 34:1 SM blocked CD1a tetramer binding to T cells
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in all human subjects tested. Thus, cellular CD1a selectively captures a particular endogenous lipid that broadly blocks its binding to TCRs. Crystal structures show that the short cellular SMs stabilized a triad of surface residues to remain flush with CD1a, but the longer lipids forced the phosphocholine group to ride above the display platform to hinder TCR approach. Whereas nearly all models emphasize antigen-mediated T cell activation, we propose that the CD1a system has intrinsic autoreactivity and is negatively regulated by natural endogenous inhibitors selectively bound in its cleft. Further, the detailed chemical structures of natural blockers could guide future design of therapeutic blockers of CD1a response.
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Keywords: General Medicine
ISSN: 0022-1007
Publisher: Rockefeller University Press
Note: Funding Information: This work was supported by the Wellcome Trust Collaborative Award (G. Ogg, J. Rossjohn, G.S. Besra, D.B. Moody), the Medical Research Council (G. Ogg and MR/R001154/1 and MR/ S000542/1 to G.S. Besra), the National Institute for Health Research Oxford Biomedical Research Centre (G. Ogg), an Australian Research Council Laureate Fellowship (J. Rossjohn), Comprehensive Research Network (G. Ogg), The Gillian Reny Stepping Strong Center for Trauma (D.P. Orgill), and the National Institutes of Health (R01 AR048632 to D.B. Moody; R01 AR074037 to A. De Jong; P30AR069625 and R01AI127654 to R.A. Clark). J.D. Altman is supported by National Institutes of Health contract HHSN272201300006C. G.S. Besra acknowledges support in the form of a Personal Research Chair from Mr. James Bardrick. Funding Information: Disclosures: R.N. Cotton reported personal fees from MPM Capital outside the submitted work. G. Ogg reported grants from UCB outside the submitted work. No other disclosures were reported. Publisher Copyright: © 2021 Cotton et al.
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