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Selective imprinting of gut-homing T cells by Peyer's patch dendritic cells

Nature volume 424, pages 88–93 (2003)Cite this article

Abstract

Whereas naive T cells migrate only to secondary lymphoid organs1,2, activation by antigen confers to T cells the ability to home to non-lymphoid sites3,4. Activated effector/memory T cells migrate preferentially to tissues that are connected to the secondary lymphoid organs where antigen was first encountered5,6,7. Thus, oral antigens induce effector/memory cells that express essential receptors for intestinal homing, namely the integrin α4β7 and CCR9, the receptor for the gut-associated chemokine TECK/CCL25 (refs 6, 8, 9). Here we show that this imprinting of gut tropism is mediated by dendritic cells from Peyer's patches. Stimulation of CD8-expressing T cells by dendritic cells from Peyer's patches, peripheral lymph nodes and spleen induced equivalent activation markers and effector activity in T cells, but only Peyer's patch dendritic cells induced high levels of α4β7, responsiveness to TECK and the ability to home to the small intestine. These findings establish that Peyer's patch dendritic cells imprint gut-homing specificity on T cells, and thus license effector/memory cells to access anatomical sites most likely to contain their cognate antigen.

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Figure 1: Antigen stimulation of CD8+ cells by DCs from PP, spleen and PLN induces equivalent activation markers and effector activity, but only PP DCs induce high expression of α4β7 integrin.
Figure 2: CD8PP-DC are significantly more responsive than CD8PLN-DC or CD8Sp-DC to the gut-associated chemokine TECK/CCL25.
Figure 3: CD8PP-DC home to the small intestine.

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References

  1. Butcher, E. C., Williams, M., Youngman, K., Rott, L. & Briskin, M. Lymphocyte trafficking and regional immunity. Adv. Immunol. 72, 209–253 (1999)

    Article  CAS  PubMed  Google Scholar 

  2. von Andrian, U. H. & Mackay, C. R. T-cell function and migration. Two sides of the same coin. N. Engl. J. Med. 343, 1020–1034 (2000)

    Article  CAS  PubMed  Google Scholar 

  3. Masopust, D., Vezys, V., Marzo, A. L. & Lefrancois, L. Preferential localization of effector memory cells in nonlymphoid tissue. Science 291, 2413–2417 (2001)

    Article  ADS  CAS  PubMed  Google Scholar 

  4. Weninger, W., Manjunath, N. & von Andrian, U. H. Migration and differentiation of CD8+ T cells. Immunol. Rev. 186, 221–233 (2002)

    Article  CAS  PubMed  Google Scholar 

  5. Guy-Grand, D., Griscelli, C. & Vassalli, P. The mouse gut T lymphocyte, a novel type of T cell. Nature, origin, and traffic in mice in normal and graft-versus-host conditions. J. Exp. Med. 148, 1661–1677 (1978)

    Article  CAS  PubMed  Google Scholar 

  6. Kantele, A., Zivny, J., Hakkinen, M., Elson, C. O. & Mestecky, J. Differential homing commitments of antigen-specific T cells after oral or parenteral immunization in humans. J. Immunol. 162, 5173–5177 (1999)

    CAS  PubMed  Google Scholar 

  7. 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  PubMed  PubMed Central  Google Scholar 

  8. Hamann, A., Andrew, D. P., Jablonski-Westrich, D., Holzmann, B. & Butcher, E. C. Role of α4-integrins in lymphocyte homing to mucosal tissues in vivo. J. Immunol. 152, 3282–3293 (1994)

    CAS  PubMed  Google Scholar 

  9. Svensson, M. et al. CCL25 mediates the localization of recently activated CD8αβ+ lymphocytes to the small-intestinal mucosa. J. Clin. Invest. 110, 1113–1121 (2002)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Davenport, M. P., Grimm, M. C. & Lloyd, A. R. A homing selection hypothesis for T-cell trafficking. Immunol. Today 21, 315–317 (2000)

    Article  CAS  PubMed  Google Scholar 

  11. Shi, G. P. et al. Cathepsin S required for normal MHC class II peptide loading and germinal center development. Immunity 10, 197–206 (1999)

    Article  CAS  PubMed  Google Scholar 

  12. Nakache, M., Berg, E. L., Streeter, P. R. & Butcher, E. C. The mucosal vascular addressin is a tissue-specific endothelial cell adhesion molecule for circulating lymphocytes. Nature 337, 179–181 (1989)

    Article  ADS  CAS  PubMed  Google Scholar 

  13. Berlin, C. et al. α4 integrins mediate lymphocyte attachment and rolling under physiologic flow. Cell 80, 413–422 (1995)

    Article  CAS  PubMed  Google Scholar 

  14. Schott, E. & Ploegh, H. L. Mouse MHC class I tetramers that are unable to bind to CD8 reveal the need for CD8 engagement in order to activate naive CD8 T cells. Eur. J. Immunol. 32, 3425–3434 (2002)

    Article  CAS  PubMed  Google Scholar 

  15. 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  PubMed  Google Scholar 

  16. Andrew, D. P. et al. Distinct but overlapping epitopes are involved in α4β7-mediated adhesion to vascular cell adhesion molecule-1, mucosal addressin-1, fibronectin, and lymphocyte aggregation. J. Immunol. 153, 3847–3861 (1994)

    CAS  PubMed  Google Scholar 

  17. Hynes, R. O. Integrins: bidirectional, allosteric signaling machines. Cell 110, 673–687 (2002)

    Article  CAS  PubMed  Google Scholar 

  18. Zabel, B. A. et al. Human G protein-coupled receptor GPR-9-6/CC chemokine receptor 9 is selectively expressed on intestinal homing T lymphocytes, mucosal lymphocytes, and thymocytes and is required for thymus-expressed chemokine-mediated chemotaxis. J. Exp. Med. 190, 1241–1256 (1999)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Zaballos, A., Gutierrez, J., Varona, R., Ardavin, C. & Marquez, G. Cutting edge: identification of the orphan chemokine receptor GPR-9-6 as CCR9, the receptor for the chemokine TECK. J. Immunol. 162, 5671–5675 (1999)

    CAS  PubMed  Google Scholar 

  20. Carramolino, L. et al. Expression of CCR9 β-chemokine receptor is modulated in thymocyte differentiation and is selectively maintained in CD8+ T cells from secondary lymphoid organs. Blood 97, 850–857 (2001)

    Article  CAS  PubMed  Google Scholar 

  21. Iwasaki, A. & Kelsall, B. L. Localization of distinct Peyer's patch dendritic cell subsets and their recruitment by chemokines macrophage inflammatory protein (MIP)-3α, MIP-3β, and secondary lymphoid organ chemokine. J. Exp. Med. 191, 1381–1394 (2000)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Wagner, N. et al. Critical role for β7 integrins in formation of the gut-associated lymphoid tissue. Nature 382, 366–370 (1996)

    Article  ADS  CAS  PubMed  Google Scholar 

  23. Weninger, W., Crowley, M. A., Manjunath, N. & von Andrian, U. H. Migratory properties of naive, effector, and memory CD8+ T cells. J. Exp. Med. 194, 953–966 (2001)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  25. Kelsall, B. L., Biron, C. A., Sharma, O. & Kaye, P. M. Dendritic cells at the host–pathogen interface. Nature Immunol. 3, 699–702 (2002)

    Article  CAS  Google Scholar 

  26. Banchereau, J. et al. Immunobiology of dendritic cells. Annu. Rev. Immunol. 18, 767–811 (2000)

    Article  CAS  PubMed  Google Scholar 

  27. Xie, H., Lim, Y. C., Luscinskas, F. W. & Lichtman, A. H. Acquisition of selectin binding and peripheral homing properties by CD4+ and CD8+ T cells. J. Exp. Med. 189, 1765–1776 (1999)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Maurice, M. M., Gould, D. S., Carroll, J., Vugmeyster, Y. & Ploegh, H. L. Positive selection of an MHC class-I restricted TCR in the absence of classical MHC class I molecules. Proc. Natl Acad. Sci. USA 98, 7437–7442 (2001)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  29. Suss, G. & Shortman, K. A subclass of dendritic cells kills CD4 T cells via Fas/Fas-ligand-induced apoptosis. J. Exp. Med. 183, 1789–1796 (1996)

    Article  CAS  PubMed  Google Scholar 

  30. Manjunath, N. et al. A transgenic mouse model to analyse CD8+ effector T cell differentiation in vivo. Proc. Natl Acad. Sci. USA 96, 13932–13937 (1999)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We are grateful to H. Ploegh for providing reagents and mice. We thank I. Dodge, B. Harnisch, G. Cheng, N. Barteneva, C. Halin, E. Schott and S. Feske for advice and technical assistance. J.R.M. is indebted to Ingrid Ramos for constant support. This work was supported by grants from NIH to U.H.v.A.; from Fondecyt to J.R.M., M.R.B. and M.R.; and from MIFAB (financed in part by Ministerio de Planificación y Cooperación, Chile) to M.R. W.W. is a fellow of the Max Kade Foundation. J.R.M. was supported in part by fellowships from Fundación Andes and the Pew Foundation.

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Authors and Affiliations

  1. The Center for Blood Research and Department of Pathology, Harvard Medical School, Boston, Massachusetts, 02115, USA

    J. Rodrigo Mora, N. Manjunath, Wolfgang Weninger, Lois L. Cavanagh & Ulrich H. von Andrian

  2. Laboratorio de Inmunología, Facultad de Ciencias, Universidad de Chile, Fundación Ciencia para la Vida, and Millennium Institute for Fundamental and Applied Biology (MIFAB), 6842301, Santiago, Chile

    Maria Rosa Bono & Mario Rosemblatt

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Correspondence to Ulrich H. von Andrian.

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Mora, J., Bono, M., Manjunath, N. et al. Selective imprinting of gut-homing T cells by Peyer's patch dendritic cells. Nature 424, 88–93 (2003). https://doi.org/10.1038/nature01726

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