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DCs metabolize sunlight-induced vitamin D3 to 'program' T cell attraction to the epidermal chemokine CCL27

Nature Immunology volume 8, pages 285–293 (2007)Cite this article

Abstract

During adaptive immune responses, dendritic cells activate T cells and endow them with specific homing properties. Mechanisms that 'imprint' specific tropisms, however, are not well defined. We show here that 1,25(OH)2D3, the active form of vitamin D3, signaled T cells to express CC chemokine receptor 10, which enabled them to migrate to the skin-specific chemokine CCL27 secreted by keratinocytes of the epidermis. In contrast, 1,25(OH)2D3 suppressed the gut-homing receptors α4β7 and CCR9. Vitamin D3, the inactive prohormone naturally generated in the skin by exposure to the sun, was processed by dendritic cells and T cells to the active metabolite, providing a mechanism for the local regulation of T cell 'epidermotropism'. Our findings support a model in which dendritic cells process and 'interpret' locally produced metabolites to 'program' T cell homing and microenvironmental positioning.

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Figure 1: Induction of CCR10 by 1,25(OH)2D3 on activated T cells.
Figure 2: Suppression of the activation-induced and retinoic acid–induced expression of α4β7 and CCR9 by 1,25(OH)2D3.
Figure 3: Distinct IL-12 requirements for induction of CCR10 in naive, previously activated and memory T cells.
Figure 4: Expression of genes encoding vitamin D3–metabolizing enzymes.
Figure 5: Ability of activated T cells, DCs, or T cell–DC cocultures to use vitamin D or its metabolites to generate active 1,25(OH)2D3.
Figure 6: Ability of activated T cells, DCs or T cell–DC cocultures to use vitamin D metabolites to induce CCR10 expression.

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References

  1. Kunkel, E.J. & Butcher, E.C. Chemokines and the tissue-specific migration of lymphocytes. Immunity 16, 1–4 (2002).

    Article  CAS  Google Scholar 

  2. Morales, J. et al. CTACK, a skin-associated chemokine that preferentially attracts skin-homing memory T cells. Proc. Natl. Acad. Sci. USA 96, 14470–14475 (1999).

    Article  CAS  Google Scholar 

  3. Homey, B. et al. CCL27–CCR10 interactions regulate T cell–mediated skin inflammation. Nat. Med. 8, 157–165 (2002).

    Article  CAS  Google Scholar 

  4. Reiss, Y., Proudfoot, A.E., Power, C.A., Campbell, J.J. & Butcher, E.C. CC chemokine receptor (CCR)4 and the CCR10 ligand cutaneous T cell-attracting chemokine (CTACK) in lymphocyte trafficking to inflamed skin. J. Exp. Med. 194, 1541–1547 (2001).

    Article  CAS  Google Scholar 

  5. MacLaughlin, J.A., Anderson, R.R. & Holick, M.F. Spectral character of sunlight modulates photosynthesis of previtamin D3 and its photoisomers in human skin. Science 216, 1001–1003 (1982).

    Article  CAS  Google Scholar 

  6. Webb, A.R. & Holick, M.F. The role of sunlight in the cutaneous production of vitamin D3. Annu. Rev. Nutr. 8, 375–399 (1988).

    Article  CAS  Google Scholar 

  7. Holick, M.F. et al. Photosynthesis of previtamin D3 in human skin and the physiologic consequences. Science 210, 203–205 (1980).

    Article  CAS  Google Scholar 

  8. Haddad, J.G., Matsuoka, L.Y., Hollis, B.W., Hu, Y.Z. & Wortsman, J. Human plasma transport of vitamin D after its endogenous synthesis. J. Clin. Invest. 91, 2552–2555 (1993).

    Article  CAS  Google Scholar 

  9. Prosser, D.E. & Jones, G. Enzymes involved in the activation and inactivation of vitamin D. Trends Biochem. Sci. 29, 664–673 (2004).

    Article  CAS  Google Scholar 

  10. van Etten, E. & Mathieu, C. Immunoregulation by 1,25-dihydroxyvitamin D3: Basic concepts. J. Steroid Biochem. Mol. Biol. 97, 93–101 (2005).

    Article  CAS  Google Scholar 

  11. Liu, P.T. et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 311, 1770–1773 (2006).

    Article  CAS  Google Scholar 

  12. Cantorna, M.T. & Mahon, B.D. D-hormone and the immune system. J. Rheumatol. Suppl. 76, 11–20 (2005).

    CAS  Google Scholar 

  13. Mangelsdorf, D.J. & Evans, R.M. The RXR heterodimers and orphan receptors. Cell 83, 841–850 (1995).

    Article  CAS  Google Scholar 

  14. Mora, J.R. et al. Selective imprinting of gut-homing T cells by Peyer's patch dendritic cells. Nature 424, 88–93 (2003).

    Article  CAS  Google Scholar 

  15. Iwata, M. et al. Retinoic acid imprints gut-homing specificity on T cells. Immunity 21, 527–538 (2004).

    Article  CAS  Google Scholar 

  16. Stagg, A.J., Kamm, M.A. & Knight, S.C. Intestinal dendritic cells increase T cell expression of α4β7 integrin. Eur. J. Immunol. 32, 1445–1454 (2002).

    Article  CAS  Google Scholar 

  17. Soler, D., Humphreys, T.L., Spinola, S.M. & Campbell, J.J. CCR4 versus CCR10 in human cutaneous TH lymphocyte trafficking. Blood 101, 1677–1682 (2003).

    Article  CAS  Google Scholar 

  18. Kang, K. et al. IL-12 synthesis by human Langerhans cells. J. Immunol. 156, 1402–1407 (1996).

    CAS  PubMed  Google Scholar 

  19. Muller, G. et al. Identification and induction of human keratinocyte-derived IL-12. J. Clin. Invest. 94, 1799–1805 (1994).

    Article  CAS  Google Scholar 

  20. Vieth, R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am. J. Clin. Nutr. 69, 842–856 (1999).

    Article  CAS  Google Scholar 

  21. Rottman, J.B., Smith, T.L., Ganley, K.G., Kikuchi, T. & Krueger, J.G. Potential role of the chemokine receptors CXCR3, CCR4, and the integrin αEβ7 in the pathogenesis of psoriasis vulgaris. Lab. Invest. 81, 335–347 (2001).

    Article  CAS  Google Scholar 

  22. Picker, L.J., Michie, S.A., Rott, L.S. & Butcher, E.C. A unique phenotype of skin-associated lymphocytes in humans. Preferential expression of the HECA-452 epitope by benign and malignant T cells at cutaneous sites. Am. J. Pathol. 136, 1053–1068 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Berg, E.L. et al. The cutaneous lymphocyte antigen is a skin lymphocyte homing receptor for the vascular lectin endothelial cell-leukocyte adhesion molecule 1. J. Exp. Med. 174, 1461–1466 (1991).

    Article  CAS  Google Scholar 

  24. Hudak, S. et al. Immune surveillance and effector functions of CCR10+ skin homing T cells. J. Immunol. 169, 1189–1196 (2002).

    Article  CAS  Google Scholar 

  25. Ohyama, Y. et al. Identification of a vitamin D-responsive element in the 5′-flanking region of the rat 25-hydroxyvitamin D3 24-hydroxylase gene. J. Biol. Chem. 269, 10545–10550 (1994).

    CAS  PubMed  Google Scholar 

  26. Lomri, A. & Baron, R. 1α,25-Dihydroxyvitamin D3 regulates the transcription of carbonic anhydrase II mRNA in avian myelomonocytes. Proc. Natl. Acad. Sci. USA 89, 4688–4692 (1992).

    Article  CAS  Google Scholar 

  27. Quelo, I., Machuca, I. & Jurdic, P. Identification of a vitamin D response element in the proximal promoter of the chicken carbonic anhydrase II gene. J. Biol. Chem. 273, 10638–10646 (1998).

    Article  CAS  Google Scholar 

  28. Kupper, T.S. & Fuhlbrigge, R.C. Immune surveillance in the skin: mechanisms and clinical consequences. Nat. Rev. Immunol. 4, 211–222 (2004).

    Article  CAS  Google Scholar 

  29. Sallusto, F. Origin and migratory properties of dendritic cells in the skin. Curr. Opin. Allergy Clin. Immunol. 1, 441–448 (2001).

    Article  CAS  Google Scholar 

  30. Mora, J.R. et al. Reciprocal and dynamic control of CD8 T cell homing by dendritic cells from skin- and gut-associated lymphoid tissues. J. Exp. Med. 201, 303–316 (2005).

    Article  CAS  Google Scholar 

  31. Guo, Y., Strugnell, S., Back, D.W. & Jones, G. Transfected human liver cytochrome P-450 hydroxylates vitamin D analogs at different side-chain positions. Proc. Natl. Acad. Sci. USA 90, 8668–8672 (1993).

    Article  CAS  Google Scholar 

  32. Pan, J. et al. A novel chemokine ligand for CCR10 and CCR3 expressed by epithelial cells in mucosal tissues. J. Immunol. 165, 2943–2949 (2000).

    Article  CAS  Google Scholar 

  33. Nemanic, M.K. et al. In vitro synthesis of vitamin D3 by cultured human keratinocytes and fibroblasts: action spectrum and effect of AY-9944. Biochim. Biophys. Acta 841, 267–277 (1985).

    Article  CAS  Google Scholar 

  34. Stoffels, K. et al. Immune regulation of 25-hydroxyvitamin-D3-1α-hydroxylase in human monocytes. J. Bone Miner. Res. 21, 37–47 (2006).

    Article  CAS  Google Scholar 

  35. Fritsche, J., Mondal, K., Ehrnsperger, A., Andreesen, R. & Kreutz, M. Regulation of 25-hydroxyvitamin D3-1α-hydroxylase and production of 1α,25-dihydroxyvitamin D3 by human dendritic cells. Blood 102, 3314–3316 (2003).

    Article  CAS  Google Scholar 

  36. Campbell, J.J. et al. The chemokine receptor CCR4 in vascular recognition by cutaneous but not intestinal memory T cells. Nature 400, 776–780 (1999).

    Article  CAS  Google Scholar 

  37. Homey, B. et al. Up-regulation of macrophage inflammatory protein-3α/CCL20 and CC chemokine receptor 6 in psoriasis. J. Immunol. 164, 6621–6632 (2000).

    Article  CAS  Google Scholar 

  38. Gombert, M. et al. CCL1–CCR8 interactions: an axis mediating the recruitment of T cells and Langerhans-type dendritic cells to sites of atopic skin inflammation. J. Immunol. 174, 5082–5091 (2005).

    Article  CAS  Google Scholar 

  39. Clark, R.A. et al. The vast majority of CLA+ T cells are resident in normal skin. J. Immunol. 176, 4431–4439 (2006).

    Article  CAS  Google Scholar 

  40. Schaerli, P. et al. A skin-selective homing mechanism for human immune surveillance T cells. J. Exp. Med. 199, 1265–1275 (2004).

    Article  CAS  Google Scholar 

  41. Kunkel, E.J. et al. CCR10 expression is a common feature of circulating and mucosal epithelial tissue IgA Ab-secreting cells. J. Clin. Invest. 111, 1001–1010 (2003).

    Article  CAS  Google Scholar 

  42. Leung, D.Y. et al. Bacterial superantigens induce T cell expression of the skin-selective homing receptor, the cutaneous lymphocyte-associated antigen, via stimulation of interleukin 12 production. J. Exp. Med. 181, 747–753 (1995).

    Article  CAS  Google Scholar 

  43. Sigmundsdottir, H., Johnston, A., Gudjonsson, J.E. & Valdimarsson, H. Differential effects of interleukin 12 and interleukin 10 on superantigen-induced expression of cutaneous lymphocyte-associated antigen (CLA) and αEβ7 integrin (CD103) by CD8+ T cells. Clin. Immunol. 111, 119–125 (2004).

    Article  CAS  Google Scholar 

  44. Piemonti, L. et al. Vitamin D3 affects differentiation, maturation, and function of human monocyte-derived dendritic cells. J. Immunol. 164, 4443–4451 (2000).

    Article  CAS  Google Scholar 

  45. Penna, G. & Adorini, L. 1α,25-dihydroxyvitamin D3 inhibits differentiation, maturation, activation, and survival of dendritic cells leading to impaired alloreactive T cell activation. J. Immunol. 164, 2405–2411 (2000).

    Article  CAS  Google Scholar 

  46. Griffin, M.D. et al. Dendritic cell modulation by 1α,25 dihydroxyvitamin D3 and its analogs: a vitamin D receptor-dependent pathway that promotes a persistent state of immaturity in vitro and in vivo. Proc. Natl. Acad. Sci. USA 98, 6800–6805 (2001).

    Article  CAS  Google Scholar 

  47. Boonstra, A. et al. 1α,25-dihydroxyvitamin D3 has a direct effect on naive CD4+ T cells to enhance the development of Th2 cells. J. Immunol. 167, 4974–4980 (2001).

    Article  CAS  Google Scholar 

  48. Iwata, M., Eshima, Y. & Kagechika, H. Retinoic acids exert direct effects on T cells to suppress Th1 development and enhance Th2 development via retinoic acid receptors. Int. Immunol. 15, 1017–1025 (2003).

    Article  CAS  Google Scholar 

  49. Cantorna, M.T., Zhu, Y., Froicu, M. & Wittke, A. Vitamin D status, 1,25-dihydroxyvitamin D3, and the immune system. Am. J. Clin. Nutr. 80, 1717S–1720S (2004).

    Article  CAS  Google Scholar 

  50. Mathieu, C. et al. In vitro and in vivo analysis of the immune system of vitamin D receptor knockout mice. J. Bone Miner. Res. 16, 2057–2065 (2001).

    Article  CAS  Google Scholar 

  51. Carpenter, K.J. & Zhao, L. Forgotten mysteries in the early history of vitamin D. J. Nutr. 129, 923–927 (1999).

    Article  CAS  Google Scholar 

  52. Lehmann, B., Rudolph, T., Pietzsch, J. & Meurer, M. Conversion of vitamin D3 to 1α,25-dihydroxyvitamin D3 in human skin equivalents. Exp. Dermatol. 9, 97–103 (2000).

    Article  CAS  Google Scholar 

  53. Lehmann, B., Genehr, T., Knuschke, P., Pietzsch, J. & Meurer, M. UVB-induced conversion of 7-dehydrocholesterol to 1α,25-dihydroxyvitamin D3 in an in vitro human skin equivalent model. J. Invest. Dermatol. 117, 1179–1185 (2001).

    Article  CAS  Google Scholar 

  54. Harris, S.S. & Dawson-Hughes, B. Plasma vitamin D and 25OHD responses of young and old men to supplementation with vitamin D3. J. Am. Coll. Nutr. 21, 357–362 (2002).

    Article  CAS  Google Scholar 

  55. Platz, E.A. et al. Plasma 1,25-dihydroxy- and 25-hydroxyvitamin D and adenomatous polyps of the distal colorectum. Cancer Epidemiol. Biomarkers Prev. 9, 1059–1065 (2000).

    CAS  PubMed  Google Scholar 

  56. Eksteen, B. et al. Epithelial inflammation is associated with CCL28 production and the recruitment of regulatory T cells expressing CCR10. J. Immunol. 177, 593–603 (2006).

    Article  CAS  Google Scholar 

  57. Gupta, V.K., McConnell, I. & Hopkins, J. Reactivity of the CD11/CD18 workshop monoclonal antibodies in the sheep. Vet. Immunol. Immunopathol. 39, 93–102 (1993).

    Article  CAS  Google Scholar 

  58. Young, A.J., Hein, W.R. & Hay, J.B. Manual of Immunological Methods: the Comprehensive Source Book of Techniques 2039–2059 (Academic Press, San Diego, 1997).

    Google Scholar 

  59. Issekutz, T.B., Chin, W. & Hay, J.B. Lymphocyte traffic through granulomas: differences in the recovery of indium-111-labeled lymphocytes in afferent and efferent lymph. Cell. Immunol. 54, 79–86 (1980).

    Article  CAS  Google Scholar 

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Acknowledgements

We acknowledge the University of California Santa Cruz Genome Browser created by the Genome Bioinformatics Group of the University of California Santa Cruz, and thank C. Crumpton-Carswell and L. Rott for flow cytometry assistance; F. Lin for help with graphics; L. Gigliello and J. Hay (University of Toronto) for help with surgical procedures; and A. Chawla for RXR-β protein. Mouse anti–ovine CD11c was provided by A. Young (South Dakota State University). Supported by the National Institutes of Health (E.C.B.; 5 T32 AI07290-21 to H.S.), the Department of Veterans Affairs (E.C.B.), the FACS Core Facility of the Stanford Digestive Disease Center, the Arthritis Foundation (G.F.D.) and the Deutsche Forschungsgemeinschaft (C.A.).

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Author notes

  1. Hekla Sigmundsdottir and Junliang Pan: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology, Laboratory of Immunology and Vascular Biology, Stanford University School of Medicine, Stanford, 94305, California, USA

    Hekla Sigmundsdottir, Junliang Pan, Gudrun F Debes, Carsten Alt, Aida Habtezion & Eugene C Butcher

  2. The Center for Molecular Biology and Medicine, Veterans Affairs Palo Alto Health Care System, Palo Alto, 94304, California, USA

    Hekla Sigmundsdottir, Junliang Pan, Gudrun F Debes, Carsten Alt, Aida Habtezion & Eugene C Butcher

  3. Millennium Pharmaceuticals, Cambridge, 02139, Massachusetts, USA

    Dulce Soler

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  1. Hekla Sigmundsdottir
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Contributions

H.S., J.P. and E.C.B. designed and conceptualized the research; H.S. did the in vitro human experiments; J.P. did the microarray, PCR and gel-shift studies and vitamin D measurements; G.F.D. and C.A. did the sheep experiments; D.S. provided essential CCR9 and CCR10 antibodies; A.H. provided intellectual and experimental input; and H.S. and E.C.B. wrote the paper with assistance from J.P. and input from G.F.D.

Corresponding author

Correspondence to Eugene C Butcher.

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Competing interests

D.S. is an employee of Millennium Pharmaceuticals.

Supplementary information

Supplementary Fig. 1

1,25(OH)2D3 but not retinoic acid induces the expression of CCR10 on CD8+ T cells. (PDF 661 kb)

Supplementary Fig. 2

Genomic view of the CCR10 gene. (PDF 84 kb)

Supplementary Fig. 3

Chemokine receptor expression by circulating memory and in vitro activated T cell subsets. (PDF 589 kb)

Supplementary Fig. 4

Schematic summary of the proposed role of sunlight, vitamin D and dendritic cells in the induction of CCR10 on T cells. (PDF 418 kb)

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Sigmundsdottir, H., Pan, J., Debes, G. et al. DCs metabolize sunlight-induced vitamin D3 to 'program' T cell attraction to the epidermal chemokine CCL27. Nat Immunol 8, 285–293 (2007). https://doi.org/10.1038/ni1433

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