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. 1998 Sep;95(1):132–140. doi: 10.1046/j.1365-2567.1998.00546.x

A long-lasting interferon-gamma response is induced to a single inoculation of antigen-pulsed dendritic cells.

S M Dillon 1, J F Griffin 1, D N Hart 1, J D Watson 1, M A Baird 1
PMCID: PMC1364387  PMID: 9767468

Abstract

Vaccines against infectious organisms must produce not only long-lasting immunity but also the appropriate immune response to clear the infection. Obligate intracellular parasites, such as mycobacteria, require a predominantly cell-mediated immune response rather than antibody. Presentation of antigen by dendritic cells (DC) has been associated with the development of strong cell-mediated responses generating the production of interferon-gamma (IFN-gamma). This cytokine has an essential role in the elimination of mycobacteria. Therefore, we investigated both the duration and the nature of the immune response after priming with DC pulsed with mycobacterial antigen and compared this with priming using a conventional adjuvant. We used two strains of mice: C57BL/6, which inherently produces a T-helper 1 (Th1)-type response to mycobacterial antigen, and BALB/c, which does not. DC-enriched cell suspensions, purified DC or cultured bone marrow cells resembling DC (BMAPC) were prepared, pulsed overnight with PPD and injected intravenously (i.v.) into naive mice. Six and 12 weeks later, splenic T lymphocytes from these mice were challenged in vitro with antigen and their proliferative response and cytokine production was determined. Significant antigen-specific proliferation was observed in all assays on rechallenge with antigen in vitro 6 and 12 weeks after the initial priming with DC. IFN-gamma was detected in both strains but was only antigen specific in the C57BL/6 strain. Purified protein derivative (PPD)-pulsed BMAPC generated similar responses 6 weeks after priming. Thus, long-term T-lymphocyte responses and the production of IFN-gamma can be generated using a single inoculation of PPD-pulsed DC.

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Selected References

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  1. Andersen P. Host responses and antigens involved in protective immunity to Mycobacterium tuberculosis. Scand J Immunol. 1997 Feb;45(2):115–131. doi: 10.1046/j.1365-3083.1997.d01-380.x. [DOI] [PubMed] [Google Scholar]
  2. Appelberg R., Castro A. G., Pedrosa J., Silva R. A., Orme I. M., Minóprio P. Role of gamma interferon and tumor necrosis factor alpha during T-cell-independent and -dependent phases of Mycobacterium avium infection. Infect Immun. 1994 Sep;62(9):3962–3971. doi: 10.1128/iai.62.9.3962-3971.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Baird M. A., Hart D. N., Abernethy N., Watson J. D. Dendritic cell presentation of PPD and 19 kDa protein of Mycobacterium tuberculosis and emergent T helper cell phenotype. Immunol Cell Biol. 1995 Dec;73(6):537–543. doi: 10.1038/icb.1995.84. [DOI] [PubMed] [Google Scholar]
  4. Bianchi R., Grohmann U., Belladonna M. L., Silla S., Fallarino F., Ayroldi E., Fioretti M. C., Puccetti P. IL-12 is both required and sufficient for initiating T cell reactivity to a class I-restricted tumor peptide (P815AB) following transfer of P815AB-pulsed dendritic cells. J Immunol. 1996 Aug 15;157(4):1589–1597. [PubMed] [Google Scholar]
  5. Cella M., Engering A., Pinet V., Pieters J., Lanzavecchia A. Inflammatory stimuli induce accumulation of MHC class II complexes on dendritic cells. Nature. 1997 Aug 21;388(6644):782–787. doi: 10.1038/42030. [DOI] [PubMed] [Google Scholar]
  6. Celluzzi C. M., Mayordomo J. I., Storkus W. J., Lotze M. T., Falo L. D., Jr Peptide-pulsed dendritic cells induce antigen-specific CTL-mediated protective tumor immunity. J Exp Med. 1996 Jan 1;183(1):283–287. doi: 10.1084/jem.183.1.283. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Dillon S. M., Hart D. N., Abernethy N., Watson J. D., Baird M. A. Priming to mycobacterial antigen in vivo using antigen-pulsed antigen presenting cells generated in vitro is influenced by the dose and presence of IL-4 in APC cultures. Scand J Immunol. 1997 Jul;46(1):1–9. doi: 10.1046/j.1365-3083.1997.d01-88.x. [DOI] [PubMed] [Google Scholar]
  8. Flynn J. L., Chan J., Triebold K. J., Dalton D. K., Stewart T. A., Bloom B. R. An essential role for interferon gamma in resistance to Mycobacterium tuberculosis infection. J Exp Med. 1993 Dec 1;178(6):2249–2254. doi: 10.1084/jem.178.6.2249. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Fuchs E. J., Matzinger P. B cells turn off virgin but not memory T cells. Science. 1992 Nov 13;258(5085):1156–1159. doi: 10.1126/science.1439825. [DOI] [PubMed] [Google Scholar]
  10. Gilbert K. M., Weigle W. O. Tolerogenicity of resting and activated B cells. J Exp Med. 1994 Jan 1;179(1):249–258. doi: 10.1084/jem.179.1.249. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Grainger R., Hart D. N., Watson J. D., Baird M. A. Antigen-pulsed, interleukin-4-treated B cells activate primed T cells in vitro but not naive T cells in vivo. Scand J Immunol. 1995 Nov;42(5):517–523. doi: 10.1111/j.1365-3083.1995.tb03689.x. [DOI] [PubMed] [Google Scholar]
  12. Güler M. L., Gorham J. D., Hsieh C. S., Mackey A. J., Steen R. G., Dietrich W. F., Murphy K. M. Genetic susceptibility to Leishmania: IL-12 responsiveness in TH1 cell development. Science. 1996 Feb 16;271(5251):984–987. doi: 10.1126/science.271.5251.984. [DOI] [PubMed] [Google Scholar]
  13. Heufler C., Koch F., Stanzl U., Topar G., Wysocka M., Trinchieri G., Enk A., Steinman R. M., Romani N., Schuler G. Interleukin-12 is produced by dendritic cells and mediates T helper 1 development as well as interferon-gamma production by T helper 1 cells. Eur J Immunol. 1996 Mar;26(3):659–668. doi: 10.1002/eji.1830260323. [DOI] [PubMed] [Google Scholar]
  14. Huygen K., Palfliet K., Jurion F., Hilgers J., ten Berg R., Van Vooren J. P., De Bruyn J. H-2-linked control of in vitro gamma interferon production in response to a 32-kilodalton antigen (P32) of Mycobacterium bovis bacillus Calmette-Guérin. Infect Immun. 1988 Dec;56(12):3196–3200. doi: 10.1128/iai.56.12.3196-3200.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Inaba K., Inaba M., Naito M., Steinman R. M. Dendritic cell progenitors phagocytose particulates, including bacillus Calmette-Guerin organisms, and sensitize mice to mycobacterial antigens in vivo. J Exp Med. 1993 Aug 1;178(2):479–488. doi: 10.1084/jem.178.2.479. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Inaba K., Inaba M., Romani N., Aya H., Deguchi M., Ikehara S., Muramatsu S., Steinman R. M. Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/macrophage colony-stimulating factor. J Exp Med. 1992 Dec 1;176(6):1693–1702. doi: 10.1084/jem.176.6.1693. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Inaba K., Metlay J. P., Crowley M. T., Steinman R. M. Dendritic cells pulsed with protein antigens in vitro can prime antigen-specific, MHC-restricted T cells in situ. J Exp Med. 1990 Aug 1;172(2):631–640. doi: 10.1084/jem.172.2.631. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Ingulli E., Mondino A., Khoruts A., Jenkins M. K. In vivo detection of dendritic cell antigen presentation to CD4(+) T cells. J Exp Med. 1997 Jun 16;185(12):2133–2141. doi: 10.1084/jem.185.12.2133. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Jeevan A., Evans R., Brown E. L., Kripke M. L. Effect of local ultraviolet irradiation on infections of mice with Candida albicans, Mycobacterium bovis BCG, and Schistosoma mansoni. J Invest Dermatol. 1992 Jul;99(1):59–64. doi: 10.1111/1523-1747.ep12611853. [DOI] [PubMed] [Google Scholar]
  20. Julius M. H., Simpson E., Herzenberg L. A. A rapid method for the isolation of functional thymus-derived murine lymphocytes. Eur J Immunol. 1973 Oct;3(10):645–649. doi: 10.1002/eji.1830031011. [DOI] [PubMed] [Google Scholar]
  21. Kamijo R., Le J., Shapiro D., Havell E. A., Huang S., Aguet M., Bosland M., Vilcek J. Mice that lack the interferon-gamma receptor have profoundly altered responses to infection with Bacillus Calmette-Guérin and subsequent challenge with lipopolysaccharide. J Exp Med. 1993 Oct 1;178(4):1435–1440. doi: 10.1084/jem.178.4.1435. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kronin V., Vremec D., Winkel K., Classon B. J., Miller R. G., Mak T. W., Shortman K., Süss G. Are CD8+ dendritic cells (DC) veto cells? The role of CD8 on DC in DC development and in the regulation of CD4 and CD8 T cell responses. Int Immunol. 1997 Jul;9(7):1061–1064. doi: 10.1093/intimm/9.7.1061. [DOI] [PubMed] [Google Scholar]
  23. Levin D., Constant S., Pasqualini T., Flavell R., Bottomly K. Role of dendritic cells in the priming of CD4+ T lymphocytes to peptide antigen in vivo. J Immunol. 1993 Dec 15;151(12):6742–6750. [PubMed] [Google Scholar]
  24. Macatonia S. E., Hosken N. A., Litton M., Vieira P., Hsieh C. S., Culpepper J. A., Wysocka M., Trinchieri G., Murphy K. M., O'Garra A. Dendritic cells produce IL-12 and direct the development of Th1 cells from naive CD4+ T cells. J Immunol. 1995 May 15;154(10):5071–5079. [PubMed] [Google Scholar]
  25. Mayordomo J. I., Zorina T., Storkus W. J., Zitvogel L., Celluzzi C., Falo L. D., Melief C. J., Ildstad S. T., Kast W. M., Deleo A. B. Bone marrow-derived dendritic cells pulsed with synthetic tumour peptides elicit protective and therapeutic antitumour immunity. Nat Med. 1995 Dec;1(12):1297–1302. doi: 10.1038/nm1295-1297. [DOI] [PubMed] [Google Scholar]
  26. Mittal A., Mishra R. S., Nath I. Accessory cell heterogeneity in lepromatous leprosy; dendritic cells and not monocytes support T cell responses. Clin Exp Immunol. 1989 May;76(2):233–239. [PMC free article] [PubMed] [Google Scholar]
  27. Mjaaland S., Fossum S. Dendritic leucocytes pulsed with monoclonal antibody-hapten conjugates elicit vigorous primary humoral responses in vivo. Scand J Immunol. 1995 Mar;41(3):305–308. doi: 10.1111/j.1365-3083.1995.tb03569.x. [DOI] [PubMed] [Google Scholar]
  28. Mosmann T. R., Coffman R. L. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol. 1989;7:145–173. doi: 10.1146/annurev.iy.07.040189.001045. [DOI] [PubMed] [Google Scholar]
  29. Nair S. K., Snyder D., Rouse B. T., Gilboa E. Regression of tumors in mice vaccinated with professional antigen-presenting cells pulsed with tumor extracts. Int J Cancer. 1997 Mar 17;70(6):706–715. doi: 10.1002/(sici)1097-0215(19970317)70:6<706::aid-ijc13>3.0.co;2-7. [DOI] [PubMed] [Google Scholar]
  30. Nishimura T., Santa K., Yahata T., Sato N., Ohta A., Ohmi Y., Sato T., Hozumi K., Habu S. Involvement of IL-4-producing Vbeta8.2+ CD4+ CD62L- CD45RB- T cells in non-MHC gene-controlled predisposition toward skewing into T helper type-2 immunity in BALB/c mice. J Immunol. 1997 Jun 15;158(12):5698–5706. [PubMed] [Google Scholar]
  31. Paglia P., Chiodoni C., Rodolfo M., Colombo M. P. Murine dendritic cells loaded in vitro with soluble protein prime cytotoxic T lymphocytes against tumor antigen in vivo. J Exp Med. 1996 Jan 1;183(1):317–322. doi: 10.1084/jem.183.1.317. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Pancholi P., Mirza A., Schauf V., Steinman R. M., Bhardwaj N. Presentation of mycobacterial antigens by human dendritic cells: lack of transfer from infected macrophages. Infect Immun. 1993 Dec;61(12):5326–5332. doi: 10.1128/iai.61.12.5326-5332.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Pancholi P., Steinman R. M., Bhardwaj N. Dendritic cells efficiently immunoselect mycobacterial-reactive T cells in human blood, including clonable antigen-reactive precursors. Immunology. 1992 Jun;76(2):217–224. [PMC free article] [PubMed] [Google Scholar]
  34. Pierre P., Turley S. J., Gatti E., Hull M., Meltzer J., Mirza A., Inaba K., Steinman R. M., Mellman I. Developmental regulation of MHC class II transport in mouse dendritic cells. Nature. 1997 Aug 21;388(6644):787–792. doi: 10.1038/42039. [DOI] [PubMed] [Google Scholar]
  35. Sallusto F., Lanzavecchia A. Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor alpha. J Exp Med. 1994 Apr 1;179(4):1109–1118. doi: 10.1084/jem.179.4.1109. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Schuler G., Steinman R. M. Dendritic cells as adjuvants for immune-mediated resistance to tumors. J Exp Med. 1997 Oct 20;186(8):1183–1187. doi: 10.1084/jem.186.8.1183. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Takahashi H., Nakagawa Y., Yokomuro K., Berzofsky J. A. Induction of CD8+ cytotoxic T lymphocytes by immunization with syngeneic irradiated HIV-1 envelope derived peptide-pulsed dendritic cells. Int Immunol. 1993 Aug;5(8):849–857. doi: 10.1093/intimm/5.8.849. [DOI] [PubMed] [Google Scholar]
  38. Thurnher M., Ramoner R., Gastl G., Radmayr C., Böck G., Herold M., Klocker H., Bartsch G. Bacillus Calmette-Guérin mycobacteria stimulate human blood dendritic cells. Int J Cancer. 1997 Jan 6;70(1):128–134. doi: 10.1002/(sici)1097-0215(19970106)70:1<128::aid-ijc19>3.0.co;2-h. [DOI] [PubMed] [Google Scholar]
  39. Yang J., Mitsuyama M. An essential role for endogenous interferon-gamma in the generation of protective T cells against Mycobacterium bovis BCG in mice. Immunology. 1997 Aug;91(4):529–535. doi: 10.1046/j.1365-2567.1997.00288.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Zitvogel L., Mayordomo J. I., Tjandrawan T., DeLeo A. B., Clarke M. R., Lotze M. T., Storkus W. J. Therapy of murine tumors with tumor peptide-pulsed dendritic cells: dependence on T cells, B7 costimulation, and T helper cell 1-associated cytokines. J Exp Med. 1996 Jan 1;183(1):87–97. doi: 10.1084/jem.183.1.87. [DOI] [PMC free article] [PubMed] [Google Scholar]

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