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CD1a selectively captures endogenous cellular lipids that broadly block T cell response

RN. Cotton, M. Wegrecki, TY. Cheng, YL. Chen, N. Veerapen, J. Le Nours, DP. Orgill, B. Pomahac, SG. Talbot, R. Willis, JD. Altman, A. de Jong, I. Van Rhijn, RA. Clark, GS. Besra, G. Ogg, J. Rossjohn, DB. Moody

. 2021 ; 218 (7) : . [pub] 20210507

Jazyk angličtina Země Spojené státy americké

Typ dokumentu časopisecké články, Research Support, N.I.H., Extramural, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc22000891

Grantová podpora
R01 AI127654 NIAID NIH HHS - United States
P30 AR069625 NIAMS NIH HHS - United States
MR/R001154/1 Medical Research Council - United Kingdom
HHSN272201300006C NIAID NIH HHS - United States
MR/S000542/1 Medical Research Council - United Kingdom
Wellcome Trust - United Kingdom
R01 AR074037 NIAMS NIH HHS - United States
R01 AR048632 NIAMS NIH HHS - United States
Department of Health - United Kingdom

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 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.

Citace poskytuje Crossref.org

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$a 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 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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