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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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.).
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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.
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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 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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DOI: https://doi.org/10.1038/ni.2790
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