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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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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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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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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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