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CD1a on Langerhans cells controls inflammatory skin disease

Nature Immunology volume 17, pages 1159–1166 (2016)Cite this article

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Abstract

CD1a is a lipid-presenting molecule that is abundantly expressed on Langerhans cells. However, the in vivo role of CD1a has remained unclear, principally because CD1a is lacking in mice. Through the use of mice with transgenic expression of CD1a, we found that the plant-derived lipid urushiol triggered CD1a-dependent skin inflammation driven by CD4+ helper T cells that produced the cytokines IL-17 and IL-22 (TH17 cells). Human subjects with poison-ivy dermatitis had a similar cytokine signature following CD1a-mediated recognition of urushiol. Among various urushiol congeners, we identified diunsaturated pentadecylcatechol (C15:2) as the dominant antigen for CD1a-restricted T cells. We determined the crystal structure of the CD1a-urushiol (C15:2) complex, demonstrating the molecular basis of urushiol interaction with the antigen-binding cleft of CD1a. In a mouse model and in patients with psoriasis, CD1a amplified inflammatory responses that were mediated by TH17 cells that reacted to self lipid antigens. Treatment with blocking antibodies to CD1a alleviated skin inflammation. Thus, we propose CD1a as a potential therapeutic target in inflammatory skin diseases.

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Figure 1: CD1a facilitates TH17 cell–mediated skin inflammation caused by poison ivy.
Figure 2: Human subjects with poison-ivy dermatitis show urushiol-specific T cell responses mediated by CD1a.
Figure 3: Urushiol-specific T cells are primed during the sensitization phase.
Figure 4: CD1a expression on LCs is essential for the generation of TH17 cells and dermatitis.
Figure 5: Urushiol is an antigen for CD1a-restricted T cells.
Figure 6: CD1a binds and displays urushiol (C15:2) in its antigen-binding cleft.
Figure 7: Crystal structure of the CD1a-urushiol complex.
Figure 8: CD1a is a target for the treatment of psoriatic inflammation.

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References

  1. Brigl, M. & Brenner, M.B. CD1: antigen presentation and T cell function. Annu. Rev. Immunol. 22, 817–890 (2004).

    Article  CAS  PubMed  Google Scholar 

  2. Porcelli, S. et al. Recognition of cluster of differentiation 1 antigens by human CD4−CD8−cytolytic T lymphocytes. Nature 341, 447–450 (1989).

    Article  CAS  PubMed  Google Scholar 

  3. Kain, L. et al. The identification of the endogenous ligands of natural killer T cells reveals the presence of mammalian α-linked glycosylceramides. Immunity 41, 543–554 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Van Rhijn, I., Godfrey, D.I., Rossjohn, J. & Moody, D.B. Lipid and small-molecule display by CD1 and MR1. Nat. Rev. Immunol. 15, 643–654 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Agea, E. et al. Human CD1-restricted T cell recognition of lipids from pollens. J. Exp. Med. 202, 295–308 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Hunger, R.E. et al. Langerhans cells utilize CD1a and langerin to efficiently present nonpeptide antigens to T cells. J. Clin. Invest. 113, 701–708 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Moody, D.B. et al. T cell activation by lipopeptide antigens. Science 303, 527–531 (2004).

    Article  CAS  PubMed  Google Scholar 

  8. Peña-Cruz, V., Ito, S., Dascher, C.C., Brenner, M.B. & Sugita, M. Epidermal Langerhans cells efficiently mediate CD1a-dependent presentation of microbial lipid antigens to T cells. J. Invest. Dermatol. 121, 517–521 (2003).

    Article  PubMed  Google Scholar 

  9. Birkinshaw, R.W. et al. αβ T cell antigen receptor recognition of CD1a presenting self lipid ligands. Nat. Immunol. 16, 258–266 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Bourgeois, E.A. et al. Bee venom processes human skin lipids for presentation by CD1a. J. Exp. Med. 212, 149–163 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. de Jong, A. et al. CD1a-autoreactive T cells recognize natural skin oils that function as headless antigens. Nat. Immunol. 15, 177–185 (2014).

    Article  CAS  PubMed  Google Scholar 

  12. de Jong, A. et al. CD1a-autoreactive T cells are a normal component of the human αβ T cell repertoire. Nat. Immunol. 11, 1102–1109 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. de Lalla, C. et al. High-frequency and adaptive-like dynamics of human CD1 self-reactive T cells. Eur. J. Immunol. 41, 602–610 (2011).

    Article  CAS  PubMed  Google Scholar 

  14. Jarrett, R. et al. Filaggrin inhibits generation of CD1a neolipid antigens by house dust mite-derived phospholipase. Sci. Transl. Med. 8, 325ra18 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Zajonc, D.M., Elsliger, M.A., Teyton, L. & Wilson, I.A. Crystal structure of CD1a in complex with a sulfatide self antigen at a resolution of 2.15 A. Nat. Immunol. 4, 808–815 (2003).

    Article  CAS  PubMed  Google Scholar 

  16. Gomez Perdiguero, E. et al. Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature 518, 547–551 (2015).

    Article  CAS  PubMed  Google Scholar 

  17. Hoeffel, G. et al. Adult Langerhans cells derive predominantly from embryonic fetal liver monocytes with a minor contribution of yolk sac-derived macrophages. J. Exp. Med. 209, 1167–1181 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Greter, M. et al. Stroma-derived interleukin-34 controls the development and maintenance of langerhans cells and the maintenance of microglia. Immunity 37, 1050–1060 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Wang, Y. et al. IL-34 is a tissue-restricted ligand of CSF1R required for the development of Langerhans cells and microglia. Nat. Immunol. 13, 753–760 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Igyártó, B.Z. & Kaplan, D.H. Antigen presentation by Langerhans cells. Curr. Opin. Immunol. 25, 115–119 (2013).

    Article  PubMed  CAS  Google Scholar 

  21. Merad, M., Ginhoux, F. & Collin, M. Origin, homeostasis and function of Langerhans cells and other langerin-expressing dendritic cells. Nat. Rev. Immunol. 8, 935–947 (2008).

    Article  CAS  PubMed  Google Scholar 

  22. Bobr, A. et al. Acute ablation of Langerhans cells enhances skin immune responses. J. Immunol. 185, 4724–4728 (2010).

    Article  CAS  PubMed  Google Scholar 

  23. Igyártó, B.Z. et al. Skin-resident murine dendritic cell subsets promote distinct and opposing antigen-specific T helper cell responses. Immunity 35, 260–272 (2011).

    Article  PubMed  CAS  Google Scholar 

  24. Kaplan, D.H., Igyártó, B.Z. & Gaspari, A.A. Early immune events in the induction of allergic contact dermatitis. Nat. Rev. Immunol. 12, 114–124 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Lowes, M.A., Bowcock, A.M. & Krueger, J.G. Pathogenesis and therapy of psoriasis. Nature 445, 866–873 (2007).

    Article  CAS  PubMed  Google Scholar 

  26. Perera, G.K., Di Meglio, P. & Nestle, F.O. Psoriasis. Annu. Rev. Pathol. 7, 385–422 (2012).

    Article  CAS  PubMed  Google Scholar 

  27. Walker, S.L., Lear, J.T. & Beck, M.H. Toxicodendron dermatitis in the UK. Int. J. Dermatol. 45, 810–813 (2006).

    Article  CAS  PubMed  Google Scholar 

  28. Kalish, R.S. The use of human T-lymphocyte clones to study T-cell function in allergic contact dermatitis to urushiol. J. Invest. Dermatol. 94 (Suppl. 6), S108–S111 (1990).

    Article  Google Scholar 

  29. Kalish, R.S. & Johnson, K.L. Enrichment and function of urushiol (poison ivy)-specific T lymphocytes in lesions of allergic contact dermatitis to urushiol. J. Immunol. 145, 3706–3713 (1990).

    CAS  PubMed  Google Scholar 

  30. Kalish, R.S., Wood, J.A. & LaPorte, A. Processing of urushiol (poison ivy) hapten by both endogenous and exogenous pathways for presentation to T cells in vitro. J. Clin. Invest. 93, 2039–2047 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. van der Fits, L. et al. Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 axis. J. Immunol. 182, 5836–5845 (2009).

    Article  CAS  PubMed  Google Scholar 

  32. Wakabayashi, T. et al. IFN-γ and TNF-α are involved in urushiol-induced contact hypersensitivity in mice. Immunol. Cell Biol. 83, 18–24 (2005).

    Article  CAS  PubMed  Google Scholar 

  33. Illing, P.T. et al. Immune self-reactivity triggered by drug-modified HLA-peptide repertoire. Nature 486, 554–558 (2012).

    Article  CAS  PubMed  Google Scholar 

  34. Cai, Y. et al. Pivotal role of dermal IL-17-producing γδ T cells in skin inflammation. Immunity 35, 596–610 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Gray, E.E., Suzuki, K. & Cyster, J.G. Cutting edge: Identification of a motile IL-17-producing γδ T cell population in the dermis. J. Immunol. 186, 6091–6095 (2011).

    Article  CAS  PubMed  Google Scholar 

  36. Kobayashi, C. et al. GM-CSF-independent CD1a expression in epidermal Langerhans cells: evidence from human CD1A genome-transgenic mice. J. Invest. Dermatol. 132, 241–244 (2012).

    Article  CAS  PubMed  Google Scholar 

  37. Riol-Blanco, L. et al. Nociceptive sensory neurons drive interleukin-23-mediated psoriasiform skin inflammation. Nature 510, 157–161 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Stoitzner, P., Romani, N., McLellan, A.D., Tripp, C.H. & Ebner, S. Isolation of skin dendritic cells from mouse and man. Methods Mol. Biol. 595, 235–248 (2010).

    Article  PubMed  Google Scholar 

  39. Winn, M.D. et al. Overview of the CCP4 suite and current developments. Acta Crystallogr. D Biol. Crystallogr. 67, 235–242 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Bricogne, G. et al. BUSTER version 2.10.0 (Global Phasing Ltd., Cambridge, UK, 2011).

  41. Emsley, P., Lohkamp, B., Scott, W.G. & Cowtan, K. Features and development of Coot. Acta Crystallogr. D Biol. Crystallogr. 66, 486–501 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Alshehry, Z.H. et al. An efficient single phase method for the extraction of plasma lipids. Metabolites 5, 389–403 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Schittenhelm, R.B., Sian, T.C., Wilmann, P.G., Dudek, N.L. & Purcell, A.W. Revisiting the arthritogenic peptide theory: quantitative not qualitative changes in the peptide repertoire of HLA-B27 allotypes. Arthritis Rheumatol. 67, 702–713 (2015).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank M. Brenner (Brigham and Women's Hospital, Boston) for anti-CD1a; B. Moody and T.-Y. Cheng (Brigham and Women's Hospital, Boston) for K562 cells and advice on human T cell assays; A. Del Grosso (Food and Drug Administration) for natural urushiols; U. von Andrian and J. Ordovas-Montanes for advice on the preparation of skin tissue; the US National Institutes of Health (NIH) tetramer facility for CD1a monomers; and the staff at the Australian synchrotron for assistance with data collection. Supported by the National Research Foundation of Korea (2012R1A6A3A03040248 to J.H.K.), the AMOREPACIFIC Research Scholar Program (to J.H.K.), National Health and Medical Research Council of Australia (J.R. and A.W.P.), the Australian Research Council (J.R.) and the US National Institutes of Health (R01 AI083426 to F.W.).

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Author notes

  1. Ji Hyung Kim and Yu Hu: These authors contributed equally to this work.

  2. Jamie Rossjohn and Florian Winau: These authors jointly directed this work.

Authors and Affiliations

  1. Department of Microbiology and Immunobiology, Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Ji Hyung Kim, Yu Hu, Jessica Kim, Qi Wan & Florian Winau

  2. Infection and Immunity Program & Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia

    Tang Yongqing, Victoria A Hughes, Jérôme Le Nours, Elsa A Marquez, Anthony W Purcell & Jamie Rossjohn

  3. Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria, Australia

    Tang Yongqing, Victoria A Hughes, Jérôme Le Nours, Elsa A Marquez & Jamie Rossjohn

  4. Laboratory of Cell Regulation, Institute for Virus Research, Kyoto University, Kyoto, Japan

    Masahiko Sugita

  5. Institute of Infection and Immunity, Cardiff University, School of Medicine, Cardiff, UK

    Jamie Rossjohn

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Contributions

J.H.K. and Y.H. designed and performed experiments and wrote the manuscript; T.Y. performed crystallography and structural analysis; Q.W. and J.K. performed flow cytometry and helped to revise the manuscript; V.A.H., J.L.N., E.A.M. and A.W.P. performed high-performance liquid chromatography, mass spectrometry, and crystallography, and analyzed data; M.S. generated CD1a-tg mice; J.R. and F.W. designed and supervised experiments and wrote the manuscript.

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Correspondence to Jamie Rossjohn or Florian Winau.

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Integrated supplementary information

Supplementary Figure 1 Cytokine pattern in skin in response to urushiol.

Wild-type (WT) and CD1a-tg mice (n = 3 per group) were sensitized and challenged with urushiol (uru) or vehicle (veh). Quantitative real-time PCR was performed to analyze cytokine gene expression in the ear tissues obtained on day 2 after challenge. Results are presented as fold increases over vehicle-treated ear tissues from wild-type mice. Results are representative of two independent experiments (mean ± s.e.m).

Supplementary Figure 2 CD1a suppresses contact hypersensitivity mediated by IFN-γ-producing cells.

Wild-type (WT) and CD1a-tg mice (n = 3 per group) were sensitized with 0.5% DNFB by painting on the abdomen on day 0, and challenged with either 0.2% DNFB or vehicle (veh) on ears on day 5 after sensitization. (a) Ear swelling after challenge. (b) Frequencies of Gr-1hiCD11bhi granulocytes (left panel), CD4+ or CD8+ T cells among live CD45+TCRβ+ cells (middle panel), and IL-17A+ or IFN-γ+ cells among TCRβ+ cells (right panel). (c) Absolute cell numbers of CD8+ or CD4+ ab T cells, IFN-γ- or IL-17A-producing cells in ears. * P < 0.05, ** P < 0.01, *** P < 0.001, using unpaired t-test. Results are representative of three independent experiments (mean ± s.e.m).

Supplementary Figure 3 Vβ TCR subfamily profile in skin and thymus.

(a-e) Ear cells or thymocytes were isolated from wild-type (WT) or CD1a-tg mice on day 2 after urushiol C15:2 or vehicle challenge and analyzed for 15 different Vβ TCR subfamilies using flow cytometry. Relative contribution of each Vβ+ cell subset among CD45+CD3+CD4+ T cells is presented in bar graphs. (a) Vβ TCR repertoire in urushiol-treated skin. (b) Frequencies of IL-17A+ cells among Vβ2+ or Vβ4+ CD4+ T cells in ear. (c) Frequencies of Vβ2+ or Vβ4+ cells in ears from CD1a-tg versus CD1a-tg mice injected with anti-CD1a antibody. (d) Vβ TCR repertoire in vehicle-treated skin. (e) Vβ TCR repertoire in thymus. * P < 0.05, ** P < 0.01; NS, not significant, using unpaired t-test. Results are representative of two to three independent experiments (mean ± s.e.m, a,c,d).

Supplementary Figure 4 Electron-density ‘shots’ of urushiol in the antigen-binding cleft of CD1a.

(a) Fo-Fc electron density map (yellow orange) of urushiol contoured at 2.2 σ level. (b) 2Fo-Fc electron density map (blue) of urushiol contoured at 0.8 σ level.

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Kim, J., Hu, Y., Yongqing, T. et al. CD1a on Langerhans cells controls inflammatory skin disease. Nat Immunol 17, 1159–1166 (2016). https://doi.org/10.1038/ni.3523

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