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Blood-derived inflammatory dendritic cells in lymph nodes stimulate acute T helper type 1 immune responses

Abstract

T helper type 1 (TH1)-polarized immune responses, which confer protection against intracellular pathogens, are thought to be initiated by dendritic cells (DCs) that enter lymph nodes from peripheral tissues. Here we found after viral infection or immunization, inflammatory monocytes were recruited into lymph nodes directly from the blood to become CD11c+CD11bhiGr-1+ inflammatory DCs, which produced abundant interleukin 12p70 and potently stimulated TH1 responses. This monocyte extravasation required the chemokine receptor CCR2 but not the chemokine CCL2 or receptor CCR7. Thus, the accumulation of inflammatory DCs and TH1 responses were much lower in Ccr2−/− mice, were preserved in Ccl2−/− mice and were relatively higher in CCL19–CCL21-Ser–deficient plt mutant mice, in which all other lymph node DC types were fewer in number. We conclude that blood-derived inflammatory DCs are important in the development of TH1 immune responses.

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Figure 1: Enhanced immune responses in plt mice.
Figure 2: Lymph node DC subtypes in BALB/c and plt mice.
Figure 3: Accumulation of inflammatory DCs in the draining lymph nodes of plt and wild-type mice.
Figure 4: Activity of CD11bhiGr-1+ DCs.
Figure 5: Chemokine dependence of the accumulation of inflammatory DCs.
Figure 6: TH1 responses in the lymph nodes of Ccr2−/− and Ccl2−/− mice.

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References

  1. Steinman, R.M., Pack, M. & Inaba, K. Dendritic cells in the T-cell areas of lymphoid organs. Immunol. Rev. 156, 25–37 (1997).

    Article  CAS  PubMed  Google Scholar 

  2. Banchereau, J. & Steinman, R.M. Dendritic cells and the control of immunity. Nature 392, 245–252 (1998).

    Article  CAS  PubMed  Google Scholar 

  3. Villadangos, J.A. & Heath, W.R. Life cycle, migration and antigen presenting functions of spleen and lymph node dendritic cells: limitations of the Langerhans cells paradigm. Semin. Immunol. 17, 262–272 (2005).

    Article  CAS  PubMed  Google Scholar 

  4. Shortman, K. & Naik, S.H. Steady-state and inflammatory dendritic-cell development. Nat. Rev. Immunol. 7, 19–30 (2007).

    Article  CAS  PubMed  Google Scholar 

  5. Allan, R.S. et al. Migratory dendritic cells transfer antigen to a lymph node-resident dendritic cell population for efficient CTL priming. Immunity 25, 153–162 (2006).

    Article  CAS  PubMed  Google Scholar 

  6. Trinchieri, G. Interleukin-12: a proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen-specific adaptive immunity. Annu. Rev. Immunol. 13, 251–276 (1995).

    Article  CAS  PubMed  Google Scholar 

  7. Brombacher, F., Kastelein, R.A. & Alber, G. Novel IL-12 family members shed light on the orchestration of Th1 responses. Trends Immunol. 24, 207–212 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Pulendran, B. et al. Distinct dendritic cell subsets differentially regulate the class of immune response in vivo. Proc. Natl. Acad. Sci. USA 96, 1036–1041 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Maldonado-Lopez, R. et al. CD8α+ and CD8α subclasses of dendritic cells direct the development of distinct T helper cells in vivo. J. Exp. Med. 189, 587–592 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Qu, C. et al. Role of CCR8 and other chemokine pathways in the migration of monocyte-derived dendritic cells to lymph nodes. J. Exp. Med. 200, 1231–1241 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Leon, B., Lopez-Bravo, M. & Ardavin, C. Monocyte-derived dendritic cells formed at the infection site control the induction of protective T helper 1 responses against Leishmania. Immunity 26, 519–531 (2007).

    Article  CAS  PubMed  Google Scholar 

  12. Boring, L. et al. Impaired monocyte migration and reduced type 1 (Th1) cytokine responses in C–C chemokine receptor 2 knockout mice. J. Clin. Invest. 100, 2552–2561 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Peters, W., Dupuis, M. & Charo, I.F. A mechanism for the impaired IFN-γ production in C–C chemokine receptor 2 (CCR2) knockout mice: role of CCR2 in linking the innate and adaptive immune responses. J. Immunol. 165, 7072–7077 (2000).

    Article  CAS  PubMed  Google Scholar 

  14. Peters, W. et al. Chemokine receptor 2 serves an early and essential role in resistance to Mycobacterium tuberculosis. Proc. Natl. Acad. Sci. USA 98, 7958–7963 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Lu, B. et al. Abnormalities in monocyte recruitment and cytokine expression in monocyte chemoattractant protein 1-deficient mice. J. Exp. Med. 187, 601–608 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Gu, L. et al. Control of TH2 polarization by the chemokine monocyte chemoattractant protein-1. Nature 404, 407–411 (2000).

    Article  CAS  PubMed  Google Scholar 

  17. Luther, S.A. & Cyster, J.G. Chemokines as regulators of T cell differentiation. Nat. Immunol. 2, 102–107 (2001).

    Article  CAS  PubMed  Google Scholar 

  18. Geissmann, F. et al. Blood monocytes: distinct subsets, how they relate to dendritic cells, and their possible roles in the regulation of T-cell responses. Immunol. Cell Biol. 86, 398–408 (2008).

    Article  CAS  PubMed  Google Scholar 

  19. Palframan, R.T. et al. Inflammatory chemokine transport and presentation in HEV: a remote control mechanism for monocyte recruitment to lymph nodes in inflamed tissues. J. Exp. Med. 194, 1361–1373 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Nakano, H. & Gunn, M.D. Gene duplications at the chemokine locus on mouse chromosome 4: multiple strain-specific haplotypes and the deletion of secondary lymphoid-organ chemokine and EBI-1 ligand chemokine genes in the plt mutation. J. Immunol. 166, 361–369 (2001).

    Article  CAS  PubMed  Google Scholar 

  21. Nakano, H. et al. A novel mutant gene involved in T-lymphocyte-specific homing into peripheral lymphoid organs on mouse chromosome 4. Blood 91, 2886–2895 (1998).

    CAS  PubMed  Google Scholar 

  22. Gunn, M.D. et al. Mice lacking expression of secondary lymphoid organ chemokine have defects in lymphocyte homing and dendritic cell localization. J. Exp. Med. 189, 451–460 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Mori, S. et al. Mice lacking expression of the chemokines CCL21-Ser and CCL19 (plt mice) demonstrate delayed but enhanced T cell immune responses. J. Exp. Med. 193, 207–217 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Yasuda, T. et al. Chemokines CCL19 and CCL21 promote activation-induced cell death of antigen-responding T cells. Blood 109, 449–456 (2007).

    Article  CAS  PubMed  Google Scholar 

  25. Forster, R. et al. CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs. Cell 99, 23–33 (1999).

    Article  CAS  PubMed  Google Scholar 

  26. Schneider, M.A. et al. CCR7 is required for the in vivo function of CD4+ CD25+ regulatory T cells. J. Exp. Med. 204, 735–745 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ruedl, C. et al. Anatomical origin of dendritic cells determines their life span in peripheral lymph nodes. J. Immunol. 165, 4910–4916 (2000).

    Article  CAS  PubMed  Google Scholar 

  28. Naik, S.H. et al. Intrasplenic steady-state dendritic cell precursors that are distinct from monocytes. Nat. Immunol. 7, 663–671 (2006).

    Article  CAS  PubMed  Google Scholar 

  29. Varol, C. et al. Monocytes give rise to mucosal, but not splenic, conventional dendritic cells. J. Exp. Med. 204, 171–180 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Lin, K.L. et al. CCR2+ monocyte-derived dendritic cells and exudate macrophages produce influenza-induced pulmonary immune pathology and mortality. J. Immunol. 180, 2562–2572 (2008).

    Article  CAS  PubMed  Google Scholar 

  31. Ohl, L. et al. CCR7 governs skin dendritic cell migration under inflammatory and steady-state conditions. Immunity 21, 279–288 (2004).

    Article  CAS  PubMed  Google Scholar 

  32. Randolph, G.J., Angeli, V. & Swartz, M.A. Dendritic-cell trafficking to lymph nodes through lymphatic vessels. Nat. Rev. Immunol. 5, 617–628 (2005).

    Article  CAS  PubMed  Google Scholar 

  33. Itano, A.A. et al. Distinct dendritic cell populations sequentially present antigen to CD4 T cells and stimulate different aspects of cell-mediated immunity. Immunity 19, 47–57 (2003).

    Article  CAS  PubMed  Google Scholar 

  34. Allenspach, E.J. et al. Migratory and lymphoid-resident dendritic cells cooperate to efficiently prime naive CD4 T cells. Immunity 29, 795–806 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. DePaolo, R.W., Rollins, B.J., Kuziel, W. & Karpus, W.J. CC chemokine ligand 2 and its receptor regulate mucosal production of IL-12 and TGF-β in high dose oral tolerance. J. Immunol. 171, 3560–3567 (2003).

    Article  CAS  PubMed  Google Scholar 

  36. Legge, K.L. & Braciale, T.J. Lymph node dendritic cells control CD8+ T cell responses through regulated FasL expression. Immunity 23, 649–659 (2005).

    Article  CAS  PubMed  Google Scholar 

  37. Sixt, M. et al. The conduit system transports soluble antigens from the afferent lymph to resident dendritic cells in the T cell area of the lymph node. Immunity 22, 19–29 (2005).

    Article  CAS  PubMed  Google Scholar 

  38. Heer, A.K., Harris, N.L., Kopf, M. & Marsland, B.J. CD4+ and CD8+ T cells exhibit differential requirements for CCR7-mediated antigen transport during influenza infection. J. Immunol. 181, 6984–6994 (2008).

    Article  CAS  PubMed  Google Scholar 

  39. Henrickson, S.E. et al. T cell sensing of antigen dose governs interactive behavior with dendritic cells and sets a threshold for T cell activation. Nat. Immunol. 9, 282–291 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Kool, M. et al. Alum adjuvant boosts adaptive immunity by inducing uric acid and activating inflammatory dendritic cells. J. Exp. Med. 205, 869–882 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Grinnan, D. et al. Enhanced allergen-induced airway inflammation in paucity of lymph node T cell (plt) mutant mice. J. Allergy Clin. Immunol. 118, 1234–1241 (2006).

    Article  CAS  PubMed  Google Scholar 

  42. Xu, B. et al. Lack of lymphoid chemokines CCL19 and CCL21 enhances allergic airway inflammation in mice. Int. Immunol. 19, 775–784 (2007).

    Article  CAS  PubMed  Google Scholar 

  43. Nakano, H., Yanagita, M. & Gunn, M.D. CD11c+B220+Gr-1+ cells in mouse lymph nodes and spleen display characteristics of plasmacytoid dendritic cells. J. Exp. Med. 194, 1171–1178 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Nakano, H. et al. Genetic defect in T lymphocyte-specific homing into peripheral lymph nodes. Eur. J. Immunol. 27, 215–221 (1997).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank K. Nakano for technical assistance, and J. Whitesides, P. McDermott and L. Olive for cell sorting. Supported by the National Institutes of Health (AI047262 and HL085473 to M.D.G.), the Japanese Ministry of Science and Technology (1579054 to H.N., and 14021121 to T.K.), the Duke Human Vaccine Institute (H.N.), the Japan Health Sciences Foundation (KH51052 to T.K.), the Japan Society for the Promotion of Science (10670606, 12670621 to T.K.), the Japan Society for the Promotion of Science for Young Scientists (M.Y.) and the intramural branch of the National Institute of Environmental Health Sciences of the National Institutes of Health.

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H.N. and K.L.L. designed and did most experiments, analyzed and interpreted data and contributed to the writing of the manuscript; M.Y. and C.C. designed and did experiments and analyzed and interpreted data; D.N.C. and T.K. provided supervision and research support; and M.D.G. conceived and supervised the project, provided intellectual and research support, and wrote the manuscript.

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Correspondence to Michael D Gunn.

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Nakano, H., Lin, K., Yanagita, M. et al. Blood-derived inflammatory dendritic cells in lymph nodes stimulate acute T helper type 1 immune responses. Nat Immunol 10, 394–402 (2009). https://doi.org/10.1038/ni.1707

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