CD1a on Langerhans cells controls inflammatory skin disease


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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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.).

Author information




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.

Corresponding authors

Correspondence to Jamie Rossjohn or Florian Winau.

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The authors declare no competing financial interests.

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).

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