CD1 lipidomes reveal lipid-binding motifs and size-based antigen-display mechanisms

Shouxiong Huang; Adam Shahine; Tan-Yun Cheng; Yi-Ling Chen; Soo Weei Ng; Gautham R. Balaji; Rachel Farquhar; Stephanie Gras; Clare S. Hardman; John D. Altman; Nabil Tahiri; Adriaan J. Minnaard; Graham S. Ogg; Jacob A. Mayfield; Jamie Rossjohn; D. Branch Moody

doi:10.1016/j.cell.2023.08.022

CD1 lipidomes reveal lipid-binding motifs and size-based antigen-display mechanisms

Shouxiong Huang, Adam Shahine, Tan-Yun Cheng, Yi-Ling Chen, Soo Weei Ng, Gautham R. Balaji, Rachel Farquhar, Stephanie Gras, Clare S. Hardman, John D. Altman, Nabil Tahiri, Adriaan J. Minnaard, Graham S. Ogg, Jacob A. Mayfield, Jamie Rossjohn, D. Branch Moody

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

16 Citations (Scopus)

Abstract

The CD1 system binds lipid antigens for display to T cells. Here, we solved lipidomes for the four human CD1 antigen-presenting molecules, providing a map of self-lipid display. Answering a basic question, the detection of >2,000 CD1-lipid complexes demonstrates broad presentation of self-sphingolipids and phospholipids. Whereas peptide antigens are chemically processed, many lipids are presented in an unaltered form. However, each type of CD1 protein differentially edits the self-lipidome to show distinct capture motifs based on lipid length and chemical composition, suggesting general antigen display mechanisms. For CD1a and CD1d, lipid size matches the CD1 cleft volume. CD1c cleft size is more variable, and CD1b is the outlier, where ligands and clefts show an extreme size mismatch that is explained by uniformly seating two small lipids in one cleft. Furthermore, the list of compounds that comprise the integrated CD1 lipidome supports the ongoing discovery of lipid blockers and antigens for T cells.

Original language	English
Pages (from-to)	4583-4596.e13
Number of pages	13
Journal	Cell
Volume	186
Issue number	21
DOIs	https://doi.org/10.1016/j.cell.2023.08.022
Publication status	Published - 12 Oct 2023

Keywords

antigen presentation
antigen processing
CD1
dendritic cells
lipidomics
major histocompatibility complex
sphingolipids
T cell receptor
T cells

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10.1016/j.cell.2023.08.022Licence: CC BY

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Huang, S., Shahine, A., Cheng, T.-Y., Chen, Y.-L., Ng, S. W., Balaji, G. R., Farquhar, R., Gras, S., Hardman, C. S., Altman, J. D., Tahiri, N., Minnaard, A. J., Ogg, G. S., Mayfield, J. A., Rossjohn, J., & Moody, D. B. (2023). CD1 lipidomes reveal lipid-binding motifs and size-based antigen-display mechanisms. Cell, 186(21), 4583-4596.e13. https://doi.org/10.1016/j.cell.2023.08.022

@article{67f9d1270fe44fb8a6c67d8d3549a302,

title = "CD1 lipidomes reveal lipid-binding motifs and size-based antigen-display mechanisms",

abstract = "The CD1 system binds lipid antigens for display to T cells. Here, we solved lipidomes for the four human CD1 antigen-presenting molecules, providing a map of self-lipid display. Answering a basic question, the detection of >2,000 CD1-lipid complexes demonstrates broad presentation of self-sphingolipids and phospholipids. Whereas peptide antigens are chemically processed, many lipids are presented in an unaltered form. However, each type of CD1 protein differentially edits the self-lipidome to show distinct capture motifs based on lipid length and chemical composition, suggesting general antigen display mechanisms. For CD1a and CD1d, lipid size matches the CD1 cleft volume. CD1c cleft size is more variable, and CD1b is the outlier, where ligands and clefts show an extreme size mismatch that is explained by uniformly seating two small lipids in one cleft. Furthermore, the list of compounds that comprise the integrated CD1 lipidome supports the ongoing discovery of lipid blockers and antigens for T cells.",

keywords = "antigen presentation, antigen processing, CD1, dendritic cells, lipidomics, major histocompatibility complex, sphingolipids, T cell receptor, T cells",

author = "Shouxiong Huang and Adam Shahine and Tan-Yun Cheng and Yi-Ling Chen and Ng, {Soo Weei} and Balaji, {Gautham R.} and Rachel Farquhar and Stephanie Gras and Hardman, {Clare S.} and Altman, {John D.} and Nabil Tahiri and Minnaard, {Adriaan J.} and Ogg, {Graham S.} and Mayfield, {Jacob A.} and Jamie Rossjohn and Moody, {D. Branch}",

note = "Funding Information: This work was supported by the NIH (AR048632, AI115358, and 75N93020D00005), the Wellcome Trust Collaborative Award (209222/Z/17/Z), the American Lung Association (IA-629987), NHMRC (1128924, 1159272, and 2008981), the ARC (DE210101031), the Chinese Academy of Medical Sciences Innovation Fund for Medical Science (2018-I2M-2-002), the UK Medical Research Council, and the UKRI (MC_UU_00008). For open access, the authors applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. We thank Gina Bia, Lixia Han, Kelly Jeter, Kyla Ugwu, Vasanthi Govindu, Rick Willis, John Shires, and Dale Long for protein production. The study was initiated by S.H. and D.B.M. with structural validations designed by J.R. Protein expression, lipid elution, and MS analyses were designed and performed by S.H. T.-Y.C. G.S.O. C.S.H. Y.-L.C. S.W.N. and J.D.A. T.Y.C. and S.H. annotated lipids. Co-crystals and cleft modeling were carried out by A.S. R.F. G.R.B. and S.G. J.A.M. provided bioinformatic analysis. A.J.M. and N.T. synthesized mycolyl lipids. The manuscript was written by S.H. J.R. and D.B.M. with input from all authors. The authors hold intellectual property through the Massachusetts General Brigham (D.B.M. G.S.O. and J.R.; filing 29618-0390P01) and the University of Oxford (G.S.O. C.S.H. and Y.-L.C.; filings 2116709.3, 2217923.8, 2217924.6). G.S.O. collaborates with UCB and Janssen, and D.B.M. consults for Pfizer. We support inclusive, diverse, and equitable conduct of research. Funding Information: This work was supported by the NIH ( AR048632 , AI115358 , and 75N93020D00005 ), the Wellcome Trust Collaborative Award ( 209222/Z/17/Z ), the American Lung Association ( IA-629987 ), NHMRC ( 1128924 , 1159272 , and 2008981 ), the ARC ( DE210101031 ), the Chinese Academy of Medical Sciences Innovation Fund for Medical Science ( 2018-I2M-2-002 ), the UK Medical Research Council , and the UKRI ( MC_UU_00008 ). For open access, the authors applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. We thank Gina Bia, Lixia Han, Kelly Jeter, Kyla Ugwu, Vasanthi Govindu, Rick Willis, John Shires, and Dale Long for protein production. Publisher Copyright: {\textcopyright} 2023 The Authors",

year = "2023",

month = oct,

day = "12",

doi = "10.1016/j.cell.2023.08.022",

language = "English",

volume = "186",

pages = "4583--4596.e13",

journal = "Cell",

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publisher = "Cell Press",

number = "21",

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TY - JOUR

T1 - CD1 lipidomes reveal lipid-binding motifs and size-based antigen-display mechanisms

AU - Huang, Shouxiong

AU - Shahine, Adam

AU - Cheng, Tan-Yun

AU - Chen, Yi-Ling

AU - Ng, Soo Weei

AU - Balaji, Gautham R.

AU - Farquhar, Rachel

AU - Gras, Stephanie

AU - Hardman, Clare S.

AU - Altman, John D.

AU - Tahiri, Nabil

AU - Minnaard, Adriaan J.

AU - Ogg, Graham S.

AU - Mayfield, Jacob A.

AU - Rossjohn, Jamie

AU - Moody, D. Branch

N1 - Funding Information: This work was supported by the NIH (AR048632, AI115358, and 75N93020D00005), the Wellcome Trust Collaborative Award (209222/Z/17/Z), the American Lung Association (IA-629987), NHMRC (1128924, 1159272, and 2008981), the ARC (DE210101031), the Chinese Academy of Medical Sciences Innovation Fund for Medical Science (2018-I2M-2-002), the UK Medical Research Council, and the UKRI (MC_UU_00008). For open access, the authors applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. We thank Gina Bia, Lixia Han, Kelly Jeter, Kyla Ugwu, Vasanthi Govindu, Rick Willis, John Shires, and Dale Long for protein production. The study was initiated by S.H. and D.B.M. with structural validations designed by J.R. Protein expression, lipid elution, and MS analyses were designed and performed by S.H. T.-Y.C. G.S.O. C.S.H. Y.-L.C. S.W.N. and J.D.A. T.Y.C. and S.H. annotated lipids. Co-crystals and cleft modeling were carried out by A.S. R.F. G.R.B. and S.G. J.A.M. provided bioinformatic analysis. A.J.M. and N.T. synthesized mycolyl lipids. The manuscript was written by S.H. J.R. and D.B.M. with input from all authors. The authors hold intellectual property through the Massachusetts General Brigham (D.B.M. G.S.O. and J.R.; filing 29618-0390P01) and the University of Oxford (G.S.O. C.S.H. and Y.-L.C.; filings 2116709.3, 2217923.8, 2217924.6). G.S.O. collaborates with UCB and Janssen, and D.B.M. consults for Pfizer. We support inclusive, diverse, and equitable conduct of research. Funding Information: This work was supported by the NIH ( AR048632 , AI115358 , and 75N93020D00005 ), the Wellcome Trust Collaborative Award ( 209222/Z/17/Z ), the American Lung Association ( IA-629987 ), NHMRC ( 1128924 , 1159272 , and 2008981 ), the ARC ( DE210101031 ), the Chinese Academy of Medical Sciences Innovation Fund for Medical Science ( 2018-I2M-2-002 ), the UK Medical Research Council , and the UKRI ( MC_UU_00008 ). For open access, the authors applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. We thank Gina Bia, Lixia Han, Kelly Jeter, Kyla Ugwu, Vasanthi Govindu, Rick Willis, John Shires, and Dale Long for protein production. Publisher Copyright: © 2023 The Authors

PY - 2023/10/12

Y1 - 2023/10/12

N2 - The CD1 system binds lipid antigens for display to T cells. Here, we solved lipidomes for the four human CD1 antigen-presenting molecules, providing a map of self-lipid display. Answering a basic question, the detection of >2,000 CD1-lipid complexes demonstrates broad presentation of self-sphingolipids and phospholipids. Whereas peptide antigens are chemically processed, many lipids are presented in an unaltered form. However, each type of CD1 protein differentially edits the self-lipidome to show distinct capture motifs based on lipid length and chemical composition, suggesting general antigen display mechanisms. For CD1a and CD1d, lipid size matches the CD1 cleft volume. CD1c cleft size is more variable, and CD1b is the outlier, where ligands and clefts show an extreme size mismatch that is explained by uniformly seating two small lipids in one cleft. Furthermore, the list of compounds that comprise the integrated CD1 lipidome supports the ongoing discovery of lipid blockers and antigens for T cells.

AB - The CD1 system binds lipid antigens for display to T cells. Here, we solved lipidomes for the four human CD1 antigen-presenting molecules, providing a map of self-lipid display. Answering a basic question, the detection of >2,000 CD1-lipid complexes demonstrates broad presentation of self-sphingolipids and phospholipids. Whereas peptide antigens are chemically processed, many lipids are presented in an unaltered form. However, each type of CD1 protein differentially edits the self-lipidome to show distinct capture motifs based on lipid length and chemical composition, suggesting general antigen display mechanisms. For CD1a and CD1d, lipid size matches the CD1 cleft volume. CD1c cleft size is more variable, and CD1b is the outlier, where ligands and clefts show an extreme size mismatch that is explained by uniformly seating two small lipids in one cleft. Furthermore, the list of compounds that comprise the integrated CD1 lipidome supports the ongoing discovery of lipid blockers and antigens for T cells.

KW - antigen presentation

KW - antigen processing

KW - CD1

KW - dendritic cells

KW - lipidomics

KW - major histocompatibility complex

KW - sphingolipids

KW - T cell receptor

KW - T cells

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U2 - 10.1016/j.cell.2023.08.022

DO - 10.1016/j.cell.2023.08.022

M3 - Article

C2 - 37725977

AN - SCOPUS:85172423886

SN - 0092-8674

VL - 186

SP - 4583-4596.e13

JO - Cell

JF - Cell

IS - 21

ER -

CD1 lipidomes reveal lipid-binding motifs and size-based antigen-display mechanisms

Abstract

Keywords

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Other files and links

Defining the structural basis of lipid mediated T cell immunity

ARC Centre of Excellence in Advanced Molecular Imaging

Cite this

CD1 lipidomes reveal lipid-binding motifs and size-based antigen-display mechanisms

Abstract

Keywords

Access to Document

Other files and links

Projects

Defining the structural basis of lipid mediated T cell immunity

ARC Centre of Excellence in Advanced Molecular Imaging

Cite this