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CD1a-autoreactive T cells recognize natural skin oils that function as headless antigens

Nature Immunology volume 15, pages 177–185 (2014)Cite this article

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Abstract

T cells autoreactive to the antigen-presenting molecule CD1a are common in human blood and skin, but the search for natural autoantigens has been confounded by background T cell responses to CD1 proteins and self lipids. After capturing CD1a-lipid complexes, we gently eluted ligands while preserving non–ligand-bound CD1a for testing lipids from tissues. CD1a released hundreds of ligands of two types. Inhibitory ligands were ubiquitous membrane lipids with polar head groups, whereas stimulatory compounds were apolar oils. We identified squalene and wax esters, which naturally accumulate in epidermis and sebum, as autoantigens presented by CD1a. The activation of T cells by skin oils suggested that headless mini-antigens nest within CD1a and displace non-antigenic resident lipids with large head groups. Oily autoantigens naturally coat the surface of the skin; thus, this points to a previously unknown mechanism of barrier immunity.

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Figure 1: CD1a-dependent activation of T cell lines.
Figure 2: Activation of CD1a-autoreactive T cell lines by recombinant CD1a.
Figure 3: Lipid composition of eluates from CD1a.
Figure 4: Nonpolar lipid extracts activate aCD1a-autoreactive T cell line.
Figure 5: Human epidermis contains multiple lipid antigens.
Figure 6: Human sebaceous glands contain headless CD1a lipid antigens.
Figure 7: Hydrophilic head groups block recognition of antigen presented by CD1a.

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Acknowledgements

We thank C. Higgins (Columbia University) for the photo of sebaceous glands; L.L. Tan for technical support for production of the BC2 TCR; and members of the US National Institutes of Health Tetramer Facility for the preparation of CD1a. Supported by the Burroughs Wellcome Fund (D.B.M.), the Mizutani Foundation, the US National Institutes of Health (AR R01048632 and AI 049313 to D.B.M.; K08AI089858 to A.G.K.; Tetramer Facility contract HHSN272201300006C to J.D.A.), the Dermatology Foundation (A.d.J.), the American Skin Association (A.d.J.), the Australian Research Council (S.G.) and the National Health and Medical Research Council of Australia (J.R.).

Author information

Author notes

  1. Annemieke de Jong

    Present address: Present address: Department of Dermatology, Columbia University Medical Center, New York, New York, USA.,

  2. Annemieke de Jong and Tan-Yun Cheng: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Annemieke de Jong, Tan-Yun Cheng, Shouxiong Huang, Anne G Kasmar, Ildiko Van Rhijn & D Branch Moody

  2. Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Australia

    Stephanie Gras, Richard W Birkinshaw & Jamie Rossjohn

  3. Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands

    Ildiko Van Rhijn

  4. Infectious Disease Department, Boston University, Boston, Massachusetts, USA

    Victor Peña-Cruz

  5. Department of Gastrointestinal and General Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Daniel T Ruan

  6. Emory Vaccine Center, Atlanta, Georgia, USA

    John D Altman

  7. Institute of Infection and Immunity, Cardiff University, School of Medicine, Heath Park, Cardiff, UK

    Jamie Rossjohn

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Contributions

A.d.J. and D.B.M. designed research and wrote the manuscript; A.d.J. and T.-Y.C. designed and performed experiments. A.G.K. did CD1a-precipitation assays and contributed to cell-free assays. S.H. did acid stripping and reloading of CD1 eluents for T cell activation, elution and quadrupole time-of-flight mass spectrometry of CD1a ligands; V.P.-C. provided epidermal sheets for lipid extraction; D.T.R. provided thyroid tissue samples; J.D.A. provided biotinylated CD1a monomers; I.V.R. identified alleles encoding TCR α- and β-chains; S.G., R.W.B. and J.R. designed experiments and contributed surface plasmon resonance data; and J.R. assisted in preparation of the manuscript.

Corresponding authors

Correspondence to Annemieke de Jong or D Branch Moody.

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Integrated supplementary information

Supplementary Figure 1 Low pH promotes unloading of lipids from CD1a protein.

Plate-bound CD1a protein was treated with citrate buffers of indicated pH. 24h after co-incubation of BC2 T cell line with pH-treated CD1a protein, T cell activation was measured in the supernatant by IFNγ ELISA

Supplementary Figure 2 Identification of lipids eluted from recombinant CD1a proteins by collision-induced dissociation mass spectrometry and comparison with lipid standards (positive mode analysis).

Supplementary Figure 3 Identification of lipids eluted from recombinant CD1a proteins by collision-induced dissociation mass spectrometry and comparison with lipid standards (negative mode analysis).

Supplementary Figure 4 Electrospray-ionization mass spectrometry of lipids eluted from silica fraction of a TLC plate.

Comparison of collision induced dissociation mass spectrometry profiles with lipid standards

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Supplementary Figures 1–4 and Supplementary Table 1 (PDF 4720 kb)

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de Jong, A., Cheng, TY., Huang, S. et al. CD1a-autoreactive T cells recognize natural skin oils that function as headless antigens. Nat Immunol 15, 177–185 (2014). https://doi.org/10.1038/ni.2790

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