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.

  • Article
  • Published:

CD103+ lung dendritic cells (LDCs) induce stronger Th1/Th17 immunity to a bacterial lung infection than CD11bhi LDCs

Cellular & Molecular Immunology volume 15, pages 377–387 (2018)Cite this article

Abstract

Recent studies suggest differential roles for CD103+ and CD11bhi lung dendritic cells (LDCs) in host defense against viral and bacterial infections. In this study, we examined the contribution of these LDC subsets in protective immunity to chlamydial lung infection using a Chlamydia muridarum mouse infection model. We found that CD103+ LDCs showed higher expression of costimulatory molecules (CD40, CD80 and CD86) and increased production of cytokines (IL-12p70, IL-10, IL-23 and IL-6) compared with CD11bhi LDCs, but the expression of programmed death-ligand 1 (PD-L1) was similar between the two subsets. More importantly, we found, in adoptive transfer experiments, that the mice receiving CD103+ LDCs from Chlamydia-infected mice exhibited better protection than the recipients of CD11bhi LDCs, which was associated with more robust Th1/Th17 cytokine responses. In addition, in vitro experiments showed that CD103+ LDCs induced stronger IFN-γ and IL-17 responses, when cocutured with chlamydial antigen-primed CD4+ T cells, than CD11bhi LDCs. Furthermore, the blockade of PD1 in the culture of CD4+ T cells with either CD103+ or CD11bhi LDCs enhanced production of IFN-γ and IL-17. In conclusion, our data provide direct evidence that CD103+ LDCs are more potent in promoting Th1/Th17 immunity to chlamydial lung infection than CD11bhi LDCs.

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
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  1. Hafner L, Beagley K, Timms P. Chlamydia trachomatis infection: host immune responses and potential vaccines. Mucosal Immunol 2008; 1: 116–130.

    Article  CAS  Google Scholar 

  2. Yang X. Role of cytokines in Chlamydia trachomatis protective immunity and immunopathology. Curr Pharm Des 2003; 9: 67–73.

    Article  CAS  Google Scholar 

  3. Brunham RC, Rey-Ladino J. Immunology of Chlamydia infection: implications for a Chlamydia trachomatis vaccine. Nat Rev Immunol 2005; 5: 149–161.

    Article  CAS  Google Scholar 

  4. Farris CM, Morrison RP. Vaccination against Chlamydia genital infection utilizing the murine C. muridarum model. Infect Immun 2011; 79: 986–996.

    Article  CAS  Google Scholar 

  5. Bai H, Cheng J, Gao X, Joyee AG, Fan Y, Wang S et al. IL-17/Th17 promotes type 1 T cell immunity against pulmonary intracellular bacterial infection through modulating dendritic cell function. J Immunol 2009; 183: 5886–5895.

    Article  CAS  Google Scholar 

  6. Gao X, Gigoux M, Yang J, Leconte J, Yang X, Suh WK. Anti-chlamydial Th17 responses are controlled by the inducible costimulator partially through phosphoinositide 3-kinase signaling. PLoS One 2012; 7: e52657.

    Article  CAS  Google Scholar 

  7. Bai H, Gao X, Zhao L, Peng Y, Yang J, Qiao S et al. Respective IL-17A production by γδ T and Th17 cells and its implication in host defense against chlamydial lung infection. Cell Mol Immunol 2016 e-pub ahead of print 31 October 2016 doi:https://doi.org/10.1038/cmi.2016.53.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Condon TV, Sawyer RT, Fenton MJ, Riches DW. Lung dendritic cells at the innate-adaptive immune interface. J Leukoc Biol 2011; 90: 883–895.

    Article  CAS  Google Scholar 

  9. Shekhar S, Joyee AG, Gao X, Peng Y, Wang S, Yang J et al. Invariant natural killer T cells promote T cell immunity by modulating the function of lung dendritic cells during Chlamydia pneumoniae infection. J Innate Immun 2015; 7: 260–274.

    Article  CAS  Google Scholar 

  10. Sung SS, Fu Jr SM, Rose CE, Gaskin F, Ju ST, Beaty SR. A major lung CD103 (alphaE)-beta7 integrin-positive epithelial dendritic cell population expressing Langerin and tight junction proteins. J Immunol 2006; 176: 2161–2172.

    Article  CAS  Google Scholar 

  11. del Rio ML, Rodriguez-Barbosa JI, Kremmer E, Förster R. CD103− and CD103+ bronchial lymph node dendritic cells are specialized in presenting and cross-presenting innocuous antigen to CD4+ and CD8+ T cells. J Immunol 2007; 178: 6861–6866.

    Article  CAS  Google Scholar 

  12. Neyt K, Lambrecht BN. The role of lung dendritic cell subsets in immunity to respiratory viruses. Immunol Rev 2013; 255: 57–67.

    Article  Google Scholar 

  13. Guilliams M, Lambrecht BN, Hammad H. Division of labor between lung dendritic cells and macrophages in the defense against pulmonary infections. Mucosal Immunol 2013; 6: 464–473.

    Article  CAS  Google Scholar 

  14. GeurtsvanKessel CH, Willart MA, van Rijt LS, Muskens F, Kool M, Baas C et al. Clearance of influenza virus from the lung depends on migratory langerin+CD11b− but not plasmacytoid dendritic cells. J Exp Med 2008; 205: 1621–1634.

    Article  CAS  Google Scholar 

  15. Helft J, Manicassamy B, Guermonprez P, Hashimoto D, Silvin A, Agudo J et al. Cross-presenting CD103+ dendritic cells are protected from influenza virus infection. J Clin Invest 2012; 122: 4037–4047.

    Article  CAS  Google Scholar 

  16. Ballesteros-Tato A, León B, Lund FE, Randall TD. Temporal changes in dendritic cell subsets, cross-priming and costimulation via CD70 control CD8(+) T cell responses to influenza. Nat Immunol 2010; 11: 216–224.

    Article  CAS  Google Scholar 

  17. Hackstein H, Kranz S, Lippitsch A, Wachtendorf A, Kershaw O, Gruber AD et al. Modulation of respiratory dendritic cells during Klebsiella pneumonia infection. Respir Res 2013; 14: 91.

    Article  Google Scholar 

  18. Leepiyasakulchai C, Taher C, Chuquimia OD, Mazurek J, Söderberg-Naucler C, Fernández C et al. Infection rate and tissue localization of murine IL-12p40-producing monocyte-derived CD103(+) lung dendritic cells during pulmonary tuberculosis. PLoS One 2013; 8: e69287.

    Article  CAS  Google Scholar 

  19. Sérgio CA, Bertolini TB, Gembre AF, Prado RQ, Bonato VL. CD11c(+) CD103(+) cells of Mycobacterium tuberculosis-infected C57BL/6 but not of BALB/c mice induce a high frequency of interferon-γ- or interleukin-17-producing CD4(+) cells. Immunology 2015; 144: 574–586.

    Article  Google Scholar 

  20. Stary G, Olive A, Radovic-Moreno AF, Gondek D, Alvarez D, Basto PA et al. VACCINES. A mucosal vaccine against Chlamydia trachomatis generates two waves of protective memory T cells. Science 2015; 348: aaa8205.

    Article  Google Scholar 

  21. Agata Y, Kawasaki A, Nishimura H, Ishida Y, Tsubata T, Yagita H et al. Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int Immunol 1996; 8: 765–772.

    Article  CAS  Google Scholar 

  22. Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 2000; 192: 1027–1034.

    Article  CAS  Google Scholar 

  23. Latchman Y, Wood CR, Chernova T, Chaudhary D, Borde M, Chernova I et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol 2001; 2: 261–268.

    Article  CAS  Google Scholar 

  24. Fankhauser SC, Starnbach MN. PD-L1 limits the mucosal CD8+ T cell response to Chlamydia trachomatis. J Immunol 2014; 192: 1079–1090.

    Article  CAS  Google Scholar 

  25. Nishimura H, Nose M, Hiai H, Minato N, Honjo T. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 1999; 11: 141–151.

    Article  CAS  Google Scholar 

  26. Nishimura H, Okazaki T, Tanaka Y, Nakatani K, Hara M, Matsumori A et al. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science 2001; 291: 319–322.

    Article  CAS  Google Scholar 

  27. Yao S, Wang S, Zhu Y, Luo L, Zhu G, Flies S et al. PD-1 on dendritic cells impedes innate immunity against bacterial infection. Blood 2009; 113: 5811–5818.

    Article  CAS  Google Scholar 

  28. Bilenki L, Wang S, Yang J, Fan Y, Jiao L, Joyee AG et al. Adoptive transfer of CD8alpha+ dendritic cells (DC) isolated from mice infected with Chlamydia muridarum are more potent in inducing protective immunity than CD8alpha- DC. J Immunol 2006; 177: 7067–7075.

    Article  CAS  Google Scholar 

  29. Joyee AG, Qiu H, Fan Y, Wang S, Yang X. Natural killer T cells are critical for dendritic cells to induce immunity in Chlamydial pneumonia. Am J Respir Crit Care Med 2008; 178: 745–756.

    Article  CAS  Google Scholar 

  30. Dong C. TH17 cells in development: an updated view of their molecular identity and genetic programming. Nat Rev Immunol 2008; 8: 337–348.

    Article  CAS  Google Scholar 

  31. Moore-Connors JM, Fraser R, Halperin SA, Wang J. CD4+CD25+Foxp3+ regulatory T cells promote Th17 responses and genital tract inflammation upon intracellular Chlamydia muridarum infection. J Immunol 2013; 191: 3430–3439.

    Article  CAS  Google Scholar 

  32. Scott CL, Aumeunier AM, Mowat AM. Intestinal CD103+ dendritic cells: master regulators of tolerance? Trends Immunol 2011; 32: 412–419.

    Article  CAS  Google Scholar 

  33. Mazzini E, Massimiliano L, Penna G, Rescigno M. Oral tolerance can be established via gap junction transfer of fed antigens from CX3CR1+ macrophages to CD103+ dendritic cells. Immunity 2014; 40: 248–261.

    Article  CAS  Google Scholar 

  34. McDole JR, Wheeler LW, McDonald KG, Wang B, Konjufca V, Knoop KA et al. Goblet cells deliver luminal antigen to CD103+ dendritic cells in the small intestine. Nature 2012; 483: 345–349.

    Article  CAS  Google Scholar 

  35. Matteoli G, Mazzini E, Iliev ID, Mileti E, Fallarino F, Puccetti P et al. Gut CD103+ dendritic cells express indoleamine 2,3-dioxygenase which influences T regulatory/T effector cell balance and oral tolerance induction. Gut 2010; 59: 595–604.

    Article  CAS  Google Scholar 

  36. Schlitzer A, McGovern N, Teo P, Zelante T, Atarashi K, Low D et al. IRF4 transcription factor-dependent CD11b+ dendritic cells in human and mouse control mucosal IL-17 cytokine responses. Immunity 2013; 38: 970–983.

    Article  CAS  Google Scholar 

  37. Ivanov S, Fontaine J, Paget C, Macho Fernandez E, Van Maele L, Renneson J et al. Key role for respiratory CD103(+) dendritic cells, IFN-γ, and IL 17 in protection against Streptococcus pneumoniae infection in response to α-galactosylceramide. J Infect Dis 2012; 206: 723–734.

    Article  CAS  Google Scholar 

  38. Contreras V, Urien C, Guiton R, Alexandre Y, Vu Manh TP, Andrieu T et al. Existence of CD8α-like dendritic cells with a conserved functional specialization and a common molecular signature in distant mammalian species. J Immunol 2010; 185: 3313–3325.

    Article  CAS  Google Scholar 

  39. Edelson BT, KC, Juang W, Kohyama R, Benoit M, Klekotka LA et al. Peripheral CD103+ dendritic cells form a unified subset developmentally related to CD8alpha+ conventional dendritic cells. J Exp Med 2010; 207: 823–836.

    Article  CAS  Google Scholar 

  40. Yang X, HayGlass KT, Brunham RC. Genetically determined differences in IL-10 and IFN-gamma responses correlate with clearance of Chlamydia trachomatis mouse pneumonitis infection. J Immunol 1996; 156: 4338–4344.

    CAS  PubMed  Google Scholar 

  41. Pulendran B, Smith JL, Caspary G, Brasel K, Pettit D, Maraskovsky E et al. Distinct dendritic cell subsets differentially regulate the class of immune response in vivo. Proc Natl Acad Sci USA 1999; 96: 1036–1041.

    Article  CAS  Google Scholar 

  42. Maldonado-López R, De Smedt T, Pajak B, Heirman C, Thielemans K, Leo O et al. Role of CD8alpha+ and CD8alpha- dendritic cells in the induction of primary immune responses in vivo. J Leukoc Biol 1999; 66: 242–246.

    Article  Google Scholar 

  43. Gao X, Wang S, Fan Y, Bai H, Yang J, Yang X. CD8+ DC, but Not CD8(−)DC, isolated from BCG-infected mice reduces pathological reactions induced by mycobacterial challenge infection. PLoS One 2010; 5: e9281.

    Article  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the Canadian Institutes of Health Research (CIHR), Manitoba Health Research Council (MHRC) and Manitoba Institute of Child Health (MICH) to XY, who is the Canada Research Chair in Infection and Immunity.

Author information

Authors and Affiliations

  1. Department of Medical Microbiology, Faculty of Medicine, University of Manitoba, Winnipeg, MB, Canada

    Sudhanshu Shekhar, Ying Peng, Shuhe Wang & Xi Yang

  2. Department of Immunology, Faculty of Medicine, University of Manitoba, Winnipeg, MB, Canada

    Sudhanshu Shekhar, Ying Peng, Shuhe Wang & Xi Yang

Authors
  1. Sudhanshu Shekhar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ying Peng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shuhe Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xi Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xi Yang.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shekhar, S., Peng, Y., Wang, S. et al. CD103+ lung dendritic cells (LDCs) induce stronger Th1/Th17 immunity to a bacterial lung infection than CD11bhi LDCs. Cell Mol Immunol 15, 377–387 (2018). https://doi.org/10.1038/cmi.2016.68

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/cmi.2016.68

This article is cited by

Search

Advanced search

Quick links