Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Environmental cues, dendritic cells and the programming of tissue-selective lymphocyte trafficking

Nature Immunology volume 9, pages 981–987 (2008)Cite this article

Abstract

Lymphocytes are imprinted during activation with trafficking programs (combinations of adhesion and chemoattractant receptors) that target their migration to specific tissues and microenvironments. Cytokines contribute, but, for gut and skin, evolution has cleverly adapted external cues from food (vitamin A) and sunlight (ultraviolet-induced vitamin D3) to imprint lymphocyte homing to the small intestines and T cell migration into the epidermis. Dendritic cells are essential: they process the vitamins to their active metabolites (retinoic acid and 1,25(OH)2D3) for presentation with antigen to lymphocytes, and they help export environmental cues through lymphatics to draining lymph nodes, to program the trafficking and effector functions of naive T and B cells.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Vitamin A and the imprinting of small intestine trafficking.

Katie Ris-Vicari

Figure 2: Sunshine, vitamin D3 and T cell epidermotropism.

Katie Ris-Vicari

Similar content being viewed by others

References

  1. Luster, A.D., Alon, R. & von Andrian, U.H. Immune cell migration in inflammation: present and future therapeutic targets. Nat. Immunol. 6, 1182–1190 (2005).

    Article  CAS  Google Scholar 

  2. Johansson-Lindbom, B. & Agace, W.W. Generation of gut-homing T cells and their localization to the small intestinal mucosa. Immunol. Rev. 215, 226–242 (2007).

    Article  CAS  Google Scholar 

  3. Schon, M.P., Zollner, T.M. & Boehncke, W.H. The molecular basis of lymphocyte recruitment to the skin: clues for pathogenesis and selective therapies of inflammatory disorders. J. Invest. Dermatol. 121, 951–962 (2003).

    Article  Google Scholar 

  4. Butcher, E.C. The multistep model of leukocyte trafficking: a personal perspective from 15 years later. in Leukocyte Trafficking: Molecular Mechanisms, Therapeutic Targets, and Methods (eds. Hamann, A. & Engelhardt, B.) 3–13 (Wiley-VCH, Weinheim, Germany, 2005).

    Google Scholar 

  5. Butcher, E.C. & Picker, L.J. Lymphocyte homing and homeostasis. Science 272, 60–66 (1996).

    Article  CAS  Google Scholar 

  6. Stolen, C.M. et al. Absence of the endothelial oxidase AOC3 leads to abnormal leukocyte traffic in vivo. Immunity 22, 105–115 (2005).

    Article  CAS  Google Scholar 

  7. Honjo, M. et al. Lectin-like oxidized LDL receptor-1 is a cell-adhesion molecule involved in endotoxin-induced inflammation. Proc. Natl. Acad. Sci. USA 100, 1274–1279 (2003).

    Article  CAS  Google Scholar 

  8. Jalkanen, S. et al. Lymphocyte migration into the skin: the role of lymphocyte homing receptor (CD44) and endothelial cell antigen (HECA-452). J. Invest. Dermatol. 94, 786–792 (1990).

    Article  CAS  Google Scholar 

  9. Salmi, M., Tohka, S., Berg, E.L., Butcher, E.C. & Jalkanen, S. Vascular adhesion protein 1 (VAP-1) mediates lymphocyte subtype-specific, selectin-independent recognition of vascular endothelium in human lymph nodes. J. Exp. Med. 186, 589–600 (1997).

    Article  CAS  Google Scholar 

  10. Mora, J.R. Homing imprinting and immunomodulation in the gut: role of dendritic cells and retinoids. Inflamm. Bowel Dis. 14, 275–289 (2008).

    Article  Google Scholar 

  11. Salmi, M. & Jalkanen, S. Lymphocyte homing to the gut: attraction, adhesion, and commitment. Immunol. Rev. 206, 100–113 (2005).

    Article  CAS  Google Scholar 

  12. 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 

  13. Arvilommi, A.M., Salmi, M., Kalimo, K. & Jalkanen, S. Lymphocyte binding to vascular endothelium in inflamed skin revisited: a central role for vascular adhesion protein-1 (VAP-1). Eur. J. Immunol. 26, 825–833 (1996).

    Article  CAS  Google Scholar 

  14. 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 

  15. Gunther, C. et al. CCL18 is expressed in atopic dermatitis and mediates skin homing of human memory T cells. J. Immunol. 174, 1723–1728 (2005).

    Article  Google Scholar 

  16. Wardlaw, A.J., Guillen, C. & Morgan, A. Mechanisms of T cell migration to the lung. Clin. Exp. Allergy 35, 4–7 (2005).

    Article  CAS  Google Scholar 

  17. Engelhardt, B. & Ransohoff, R.M. The ins and outs of T-lymphocyte trafficking to the CNS: anatomical sites and molecular mechanisms. Trends Immunol. 26, 485–495 (2005).

    Article  CAS  Google Scholar 

  18. Kunkel, E.J. & Butcher, E.C. Plasma-cell homing. Nat. Rev. Immunol. 3, 822–829 (2003).

    Article  CAS  Google Scholar 

  19. Hieshima, K. et al. CC chemokine ligands 25 and 28 play essential roles in intestinal extravasation of IgA antibody-secreting cells. J. Immunol. 173, 3668–3675 (2004).

    Article  CAS  Google Scholar 

  20. Wilson, E. & Butcher, E.C. CCL28 controls immunoglobulin (Ig)A plasma cell accumulation in the lactating mammary gland and IgA antibody transfer to the neonate. J. Exp. Med. 200, 805–809 (2004).

    Article  CAS  Google Scholar 

  21. Butcher, E.C. The regulation of lymphocyte traffic. Curr. Top. Microbiol. Immunol. 128, 85–122 (1986).

    Article  CAS  Google Scholar 

  22. Young, A.J., Hay, J.B. & Mackay, C.R. Lymphocyte recirculation and life span in vivo. Curr. Top. Microbiol. Immunol. 184, 161–173 (1993).

    CAS  PubMed  Google Scholar 

  23. Campbell, D.J. & Butcher, E.C. Rapid acquisition of tissue-specific homing phenotypes by CD4+ T cells activated in cutaneous or mucosal lymphoid tissues. J. Exp. Med. 195, 135–141 (2002).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  25. Sigmundsdottir, H. et al. DCs metabolize sunlight-induced vitamin D3 to 'program' T cell attraction to the epidermal chemokine CCL27. Nat. Immunol. 8, 285–293 (2007).

    Article  CAS  Google Scholar 

  26. Napoli, J.L. Retinoic acid biosynthesis and metabolism. FASEB J. 10, 993–1001 (1996).

    Article  CAS  Google Scholar 

  27. Moore, T. Vitamin A and carotene. VI. The conversion of carotene to vitamin A in vivo. Biochem. J. 24, 692–702 (1930).

    Article  CAS  Google Scholar 

  28. Svensson, M. et al. Retinoic acid receptor signaling levels and antigen dose regulate gut homing receptor expression on CD8+ T cells. Mucosal Immunol. 1, 38–48 (2008).

    Article  CAS  Google Scholar 

  29. Johansson-Lindbom, B. et al. Functional specialization of gut CD103+ dendritic cells in the regulation of tissue-selective T cell homing. J. Exp. Med. 202, 1063–1073 (2005).

    Article  CAS  Google Scholar 

  30. Szatmari, I. et al. PPARγ controls CD1d expression by turning on retinoic acid synthesis in developing human dendritic cells. J. Exp. Med. 203, 2351–2362 (2006).

    Article  CAS  Google Scholar 

  31. Saurer, L., McCullough, K.C. & Summerfield, A. In vitro induction of mucosa-type dendritic cells by all-trans retinoic acid. J. Immunol. 179, 3504–3514 (2007).

    Article  CAS  Google Scholar 

  32. Stenstad, H. et al. Gut-associated lymphoid tissue-primed CD4+ T cells display CCR9-dependent and -independent homing to the small intestine. Blood 107, 3447–3454 (2006).

    Article  CAS  Google Scholar 

  33. Meurens, F. et al. Commensal bacteria and expression of two major intestinal chemokines, TECK/CCL25 and MEC/CCL28, and their receptors. PLoS ONE 2, e677 (2007).

    Article  Google Scholar 

  34. Enioutina, E.Y., Bareyan, D. & Daynes, R.A. TLR ligands that stimulate the metabolism of vitamin D3 in activated murine dendritic cells can function as effective mucosal adjuvants to subcutaneously administered vaccines. Vaccine 26, 601–613 (2008).

    Article  CAS  Google Scholar 

  35. 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 

  36. 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 

  37. 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 

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

    Article  CAS  Google Scholar 

  39. 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 

  40. 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 

  41. 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 

  42. Homey, B. et al. Cutting edge: the orphan chemokine receptor G protein-coupled receptor-2 (GPR-2, CCR10) binds the skin-associated chemokine CCL27 (CTACK/ALP/ILC). J. Immunol. 164, 3465–3470 (2000).

    Article  CAS  Google Scholar 

  43. Lazarus, N.H. et al. A common mucosal chemokine (mucosae-associated epithelial chemokine/CCL28) selectively attracts IgA plasmablasts. J. Immunol. 170, 3799–3805 (2003).

    Article  CAS  Google Scholar 

  44. Shirakawa, A.-K. et al. 1,25-Dihydroxyvitamin D3 induces CCR10 expression in terminally differentiating human B cells. J. Immunol. 180, 2786–2795 (2008).

    Article  CAS  Google Scholar 

  45. 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 

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

    Article  CAS  Google Scholar 

  47. 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 

  48. Dudda, J.C. et al. Dendritic cells govern induction and reprogramming of polarized tissue-selective homing receptor patterns of T cells: important roles for soluble factors and tissue microenvironments. Eur. J. Immunol. 35, 1056–1065 (2005).

    Article  CAS  Google Scholar 

  49. 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 

  50. 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 

  51. Adorini, L. Tolerogenic dendritic cells induced by vitamin D receptor ligands enhance regulatory T cells inhibiting autoimmune diabetes. Ann. NY Acad. Sci. 987, 258–261 (2003).

    Article  CAS  Google Scholar 

  52. Coombes, J.L. et al. A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-β and retinoic acid dependent mechanism. J. Exp. Med. 204, 1757–1764 (2007).

    Article  CAS  Google Scholar 

  53. Kang, S.G. et al. Metabolites induce gut-homing FoxP3+ regulatory T cells. J. Immunol. 179, 3724–3733 (2007).

    Article  CAS  Google Scholar 

  54. Benson, M.J., Pino-Lagos, K., Rosemblatt, M. & Noelle, R.J. All-trans retinoic acid mediates enhanced T reg cell growth, differentiation, and gut homing in the face of high levels of co-stimulation. J. Exp. Med. 204, 1765–1774 (2007).

    Article  CAS  Google Scholar 

  55. Sun, C.-M. et al. Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid. J. Exp. Med. 204, 1775–1785 (2007).

    Article  CAS  Google Scholar 

  56. Mucida, D. et al. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 317, 256–260 (2007).

    Article  CAS  Google Scholar 

  57. Gregori, S. et al. Regulatory T cells induced by 1α,25-dihydroxyvitamin D3 and mycophenolate mofetil treatment mediate transplantation tolerance. J. Immunol. 167, 1945–1953 (2001).

    Article  CAS  Google Scholar 

  58. Prystowsky, J.H., Muzio, P.J., Sevran, S. & Clemens, T.L. Effect of UVB phototherapy and oral calcitriol (1,25-dihydroxyvitamin D3) on vitamin D photosynthesis in patients with psoriasis. J. Am. Acad. Dermatol. 35, 690–695 (1996).

    Article  CAS  Google Scholar 

  59. Zhu, Y., Mahon, B.D., Froicu, M. & Cantorna, M.T. Calcium and 1α,25-dihydroxyvitamin D3 target the TNF-α pathway to suppress experimental inflammatory bowel disease. Eur. J. Immunol. 35, 217–224 (2005).

    Article  CAS  Google Scholar 

  60. Penna, G., Amuchastegui, S., Laverny, G. & Adorini, L. Vitamin D receptor agonists in the treatment of autoimmune diseases: selective targeting of myeloid but not plasmacytoid dendritic cells. J. Bone Miner. Res. 22, V69–V73 (2007).

    Article  CAS  Google Scholar 

  61. 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 

  62. Jaimes, M.C. et al. Maturation and trafficking markers on rotavirus-specific B cells during acute infection and convalescence in children. J. Virol. 78, 10967–10976 (2004).

    Article  CAS  Google Scholar 

  63. Mora, J.R. et al. Generation of gut-homing IgA-secreting B cells by intestinal dendritic cells. Science 314, 1157–1160 (2006).

    Article  CAS  Google Scholar 

  64. Kim, C.H. et al. Rules of chemokine receptor association with T cell polarization in vivo. J. Clin. Invest. 108, 1331–1339 (2001).

    Article  CAS  Google Scholar 

  65. Wagers, A.J., Waters, C.M., Stoolman, L.M. & Kansas, G.S. Interleukin 12 and interleukin 4 control T cell adhesion to endothelial selectins through opposite effects on α1,3-fucosyltransferase VII gene expression. J. Exp. Med. 188, 2225–2231 (1998).

    Article  CAS  Google Scholar 

  66. Picker, L.J. et al. Control of lymphocyte recirculation in man. II. Differential regulation of the cutaneous lymphocyte-associated antigen, a tissue-selective homing receptor for skin-homing T cells. J. Immunol. 150, 1122–1136 (1993).

    CAS  PubMed  Google Scholar 

  67. Kim, C.H., Nagata, K. & Butcher, E.C. Dendritic cells support sequential reprogramming of chemoattractant receptor profiles during naive to effector T cell differentiation. J. Immunol. 171, 152–158 (2003).

    Article  CAS  Google Scholar 

  68. Campbell, D.J., Kim, C.H. & Butcher, E.C. Separable effector T cell populations specialized for B cell help or tissue inflammation. Nat. Immunol. 2, 876–881 (2001).

    Article  CAS  Google Scholar 

  69. Huehn, J. & Hamann, A. Homing to suppress: address codes for Treg migration. Trends Immunol. 26, 632–636 (2005).

    Article  CAS  Google Scholar 

  70. Sather, B.D. et al. Altering the distribution of Foxp3+ regulatory T cells results in tissue-specific inflammatory disease. J. Exp. Med. 204, 1335–1347 (2007).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank A. Habtezion and C. Oderup for critical comments on the manuscript. Supported by Ruth L. Kirschstein National Research Service Award AI 66835-01A1 (H.S.); by US National Institutes of Health (NIH) grants AI72618, AI47822, AI059635, GM37734 and U19 AI057229 and a Merit Award from the Department of Veterans Affairs (E.C.B.); and by the FACS Core Facility of the Stanford Digestive Disease Center under NIH grant P30 DK56339.

Author information

Authors and Affiliations

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

    Hekla Sigmundsdottir & 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 & Eugene C Butcher

Authors
  1. Hekla Sigmundsdottir
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eugene C Butcher
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eugene C Butcher.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sigmundsdottir, H., Butcher, E. Environmental cues, dendritic cells and the programming of tissue-selective lymphocyte trafficking. Nat Immunol 9, 981–987 (2008). https://doi.org/10.1038/ni.f.208

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni.f.208

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing