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

Rachel N Cotton; Marcin Wegrecki; Tan-Yun Cheng; Yi-Ling Chen; Natacha Veerapen; Jérôme Le Nours; Dennis P Orgill; Bohdan Pomahac; Simon G Talbot; Richard Willis; John D Altman; Annemieke de Jong; Ildiko Van Rhijn; Rachael A Clark; Gurdyal S Besra; Graham Ogg; Jamie Rossjohn; D Branch Moody

doi:10.1084/jem.20202699

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

Rachel N Cotton, Marcin Wegrecki, Tan-Yun Cheng, Yi-Ling Chen, Natacha Veerapen, Jérôme Le Nours, Dennis P Orgill, Bohdan Pomahac, Simon G Talbot, Richard Willis, John D Altman, Annemieke de Jong, Ildiko Van Rhijn, Rachael A Clark, Gurdyal S Besra, Graham Ogg, Jamie Rossjohn, D Branch Moody

Immunology

Research output: Contribution to journal › Article › Academic › peer-review

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 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.

Original language	English
Article number	e20202699
Number of pages	20
Journal	Journal of Experimental Medicine
Volume	218
Issue number	7
DOIs	https://doi.org/10.1084/jem.20202699
Publication status	Published - 7 May 2021

Bibliographical 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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Cotton, R. N., Wegrecki, M., Cheng, T.-Y., Chen, Y.-L., Veerapen, N., Le Nours, J., Orgill, D. P., Pomahac, B., Talbot, S. G., Willis, R., Altman, J. D., de Jong, A., Van Rhijn, I., Clark, R. A., Besra, G. S., Ogg, G., Rossjohn, J., & Moody, D. B. (2021). CD1a selectively captures endogenous cellular lipids that broadly block T cell response. Journal of Experimental Medicine, 218(7), Article e20202699. https://doi.org/10.1084/jem.20202699

@article{140c68f66ecb4bd0be12a538c2fb0222,

title = "CD1a selectively captures endogenous cellular lipids that broadly block T cell response",

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 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.",

author = "Cotton, \{Rachel N\} and Marcin Wegrecki and Tan-Yun Cheng and Yi-Ling Chen and Natacha Veerapen and \{Le Nours\}, J{\'e}r{\^o}me and Orgill, \{Dennis P\} and Bohdan Pomahac and Talbot, \{Simon G\} and Richard Willis and Altman, \{John D\} and \{de Jong\}, Annemieke and \{Van Rhijn\}, Ildiko and Clark, \{Rachael A\} and Besra, \{Gurdyal S\} and Graham Ogg and Jamie Rossjohn and Moody, \{D Branch\}",

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: {\textcopyright} 2021 Cotton et al.",

year = "2021",

month = may,

day = "7",

doi = "10.1084/jem.20202699",

language = "English",

volume = "218",

journal = "Journal of Experimental Medicine",

issn = "0022-1007",

publisher = "Rockefeller University Press",

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Cotton, RN, Wegrecki, M, Cheng, T-Y, Chen, Y-L, Veerapen, N, Le Nours, J, Orgill, DP, Pomahac, B, Talbot, SG, Willis, R, Altman, JD, de Jong, A, Van Rhijn, I, Clark, RA, Besra, GS, Ogg, G, Rossjohn, J & Moody, DB 2021, 'CD1a selectively captures endogenous cellular lipids that broadly block T cell response', Journal of Experimental Medicine, vol. 218, no. 7, e20202699. https://doi.org/10.1084/jem.20202699

TY - JOUR

T1 - CD1a selectively captures endogenous cellular lipids that broadly block T cell response

AU - Cotton, Rachel N

AU - Wegrecki, Marcin

AU - Cheng, Tan-Yun

AU - Chen, Yi-Ling

AU - Veerapen, Natacha

AU - Le Nours, Jérôme

AU - Orgill, Dennis P

AU - Pomahac, Bohdan

AU - Talbot, Simon G

AU - Willis, Richard

AU - Altman, John D

AU - de Jong, Annemieke

AU - Van Rhijn, Ildiko

AU - Clark, Rachael A

AU - Besra, Gurdyal S

AU - Ogg, Graham

AU - Rossjohn, Jamie

AU - Moody, D Branch

N1 - 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.

PY - 2021/5/7

Y1 - 2021/5/7

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85105756060

U2 - 10.1084/jem.20202699

DO - 10.1084/jem.20202699

M3 - Article

C2 - 33961028

SN - 0022-1007

VL - 218

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

IS - 7

M1 - e20202699

ER -

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

Abstract

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