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. 1993 Aug 1;178(2):479–488. doi: 10.1084/jem.178.2.479

Dendritic cell progenitors phagocytose particulates, including bacillus Calmette-Guerin organisms, and sensitize mice to mycobacterial antigens in vivo

PMCID: PMC2191128  PMID: 7688024

Abstract

Dendritic cells, while effective in sensitizing T cells to several different antigens, show little or no phagocytic activity. To the extent that endocytosis is required for antigen processing and presentation, it is not evident how dendritic cells would present particle-associated peptides. Evidence has now been obtained showing that progenitors to dendritic cells can internalize particles, including Bacillus Calmette-Guerin (BCG) mycobacteria. The particulates are applied for 20 h to bone marrow cultures that have been stimulated with granulocyte/macrophage colony-stimulating factor (GM-CSF) to induce aggregates of growing dendritic cells. Cells within these aggregates are clearly phagocytic. If the developing cultures are exposed to particles, washed, and "chased" for 2 d, the number of major histocompatibility complex class II-rich dendritic cells increases substantially and at least 50% contain internalized mycobacteria or latex particles. The mycobacteria-laden, newly developed dendritic cells are much more potent in presenting antigens to primed T cells than corresponding cultures of mature dendritic cells that are exposed to a pulse of organisms. A similar situation exists when the BCG- charged dendritic cells are injected into the footpad or blood stream of naive mice. Those dendritic cells that have phagocytosed organisms induce the strongest T cell responses to mycobacterial antigens in draining lymph node and spleen. The administration of antigens to GM- CSF-induced, developing dendritic cells (by increasing both antigen uptake and cell numbers) will facilitate the use of these antigen- presenting cells for active immunization in situ.

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Selected References

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  1. Breel M., Mebius R. E., Kraal G. Dendritic cells of the mouse recognized by two monoclonal antibodies. Eur J Immunol. 1987 Nov;17(11):1555–1559. doi: 10.1002/eji.1830171105. [DOI] [PubMed] [Google Scholar]
  2. Britz J. S., Askenase P. W., Ptak W., Steinman R. M., Gershon R. K. Specialized antigen-presenting cells. Splenic dendritic cells and peritoneal-exudate cells induced by mycobacteria activate effector T cells that are resistant to suppression. J Exp Med. 1982 May 1;155(5):1344–1356. doi: 10.1084/jem.155.5.1344. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Brodsky F. M., Guagliardi L. E. The cell biology of antigen processing and presentation. Annu Rev Immunol. 1991;9:707–744. doi: 10.1146/annurev.iy.09.040191.003423. [DOI] [PubMed] [Google Scholar]
  4. Bujdoso R., Hopkins J., Dutia B. M., Young P., McConnell I. Characterization of sheep afferent lymph dendritic cells and their role in antigen carriage. J Exp Med. 1989 Oct 1;170(4):1285–1301. doi: 10.1084/jem.170.4.1285. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Cohn Z. A., Ehrenreich B. A. The uptake, storage, and intracellular hydrolysis of carbohydrates by macrophages. J Exp Med. 1969 Jan 1;129(1):201–225. doi: 10.1084/jem.129.1.201. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Crowley M., Inaba K., Steinman R. M. Dendritic cells are the principal cells in mouse spleen bearing immunogenic fragments of foreign proteins. J Exp Med. 1990 Jul 1;172(1):383–386. doi: 10.1084/jem.172.1.383. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Demotz S., Grey H. M., Sette A. The minimal number of class II MHC-antigen complexes needed for T cell activation. Science. 1990 Aug 31;249(4972):1028–1030. doi: 10.1126/science.2118680. [DOI] [PubMed] [Google Scholar]
  8. Ehrenreich B. A., Cohn Z. A. The fate of peptides pinocytosed by macrophages in vitro. J Exp Med. 1969 Jan 1;129(1):227–245. doi: 10.1084/jem.129.1.227. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Ehrenreich B. A., Cohn Z. A. The uptake and digestion of iodinated human serum albumin by macrophages in vitro. J Exp Med. 1967 Nov 1;126(5):941–958. doi: 10.1084/jem.126.5.941. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Faustman D. L., Steinman R. M., Gebel H. M., Hauptfeld V., Davie J. M., Lacy P. E. Prevention of rejection of murine islet allografts by pretreatment with anti-dendritic cell antibody. Proc Natl Acad Sci U S A. 1984 Jun;81(12):3864–3868. doi: 10.1073/pnas.81.12.3864. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Fossum S., Rolstad B. The roles of interdigitating cells and natural killer cells in the rapid rejection of allogeneic lymphocytes. Eur J Immunol. 1986 Apr;16(4):440–450. doi: 10.1002/eji.1830160422. [DOI] [PubMed] [Google Scholar]
  12. Harding C. V., Roof R. W., Unanue E. R. Turnover of Ia-peptide complexes is facilitated in viable antigen-presenting cells: biosynthetic turnover of Ia vs. peptide exchange. Proc Natl Acad Sci U S A. 1989 Jun;86(11):4230–4234. doi: 10.1073/pnas.86.11.4230. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Harding C. V., Unanue E. R. Quantitation of antigen-presenting cell MHC class II/peptide complexes necessary for T-cell stimulation. Nature. 1990 Aug 9;346(6284):574–576. doi: 10.1038/346574a0. [DOI] [PubMed] [Google Scholar]
  14. Havenith C. E., Breedijk A. J., Betjes M. G., Calame W., Beelen R. H., Hoefsmit E. C. T cell priming in situ by intratracheally instilled antigen-pulsed dendritic cells. Am J Respir Cell Mol Biol. 1993 Mar;8(3):319–324. doi: 10.1165/ajrcmb/8.3.319. [DOI] [PubMed] [Google Scholar]
  15. Holt P. G., Schon-Hegrad M. A., Oliver J. MHC class II antigen-bearing dendritic cells in pulmonary tissues of the rat. Regulation of antigen presentation activity by endogenous macrophage populations. J Exp Med. 1988 Feb 1;167(2):262–274. doi: 10.1084/jem.167.2.262. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hunt D. F., Michel H., Dickinson T. A., Shabanowitz J., Cox A. L., Sakaguchi K., Appella E., Grey H. M., Sette A. Peptides presented to the immune system by the murine class II major histocompatibility complex molecule I-Ad. Science. 1992 Jun 26;256(5065):1817–1820. doi: 10.1126/science.1319610. [DOI] [PubMed] [Google Scholar]
  17. 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]
  18. 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]
  19. Inaba K., Steinman R. M., Pack M. W., Aya H., Inaba M., Sudo T., Wolpe S., Schuler G. Identification of proliferating dendritic cell precursors in mouse blood. J Exp Med. 1992 May 1;175(5):1157–1167. doi: 10.1084/jem.175.5.1157. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Jensen P. E. Protein synthesis in antigen processing. J Immunol. 1988 Oct 15;141(8):2545–2550. [PubMed] [Google Scholar]
  21. Kraal G., Breel M., Janse M., Bruin G. Langerhans' cells, veiled cells, and interdigitating cells in the mouse recognized by a monoclonal antibody. J Exp Med. 1986 Apr 1;163(4):981–997. doi: 10.1084/jem.163.4.981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kämpgen E., Koch N., Koch F., Stöger P., Heufler C., Schuler G., Romani N. Class II major histocompatibility complex molecules of murine dendritic cells: synthesis, sialylation of invariant chain, and antigen processing capacity are down-regulated upon culture. Proc Natl Acad Sci U S A. 1991 Apr 15;88(8):3014–3018. doi: 10.1073/pnas.88.8.3014. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Liu L. M., MacPherson G. G. Antigen acquisition by dendritic cells: intestinal dendritic cells acquire antigen administered orally and can prime naive T cells in vivo. J Exp Med. 1993 May 1;177(5):1299–1307. doi: 10.1084/jem.177.5.1299. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Nonacs R., Humborg C., Tam J. P., Steinman R. M. Mechanisms of mouse spleen dendritic cell function in the generation of influenza-specific, cytolytic T lymphocytes. J Exp Med. 1992 Aug 1;176(2):519–529. doi: 10.1084/jem.176.2.519. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Pugh C. W., MacPherson G. G., Steer H. W. Characterization of nonlymphoid cells derived from rat peripheral lymph. J Exp Med. 1983 Jun 1;157(6):1758–1779. doi: 10.1084/jem.157.6.1758. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Puré E., Inaba K., Crowley M. T., Tardelli L., Witmer-Pack M. D., Ruberti G., Fathman G., Steinman R. M. Antigen processing by epidermal Langerhans cells correlates with the level of biosynthesis of major histocompatibility complex class II molecules and expression of invariant chain. J Exp Med. 1990 Nov 1;172(5):1459–1469. doi: 10.1084/jem.172.5.1459. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Reis e Sousa C., Stahl P. D., Austyn J. M. Phagocytosis of antigens by Langerhans cells in vitro. J Exp Med. 1993 Aug 1;178(2):509–519. doi: 10.1084/jem.178.2.509. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Romani N., Koide S., Crowley M., Witmer-Pack M., Livingstone A. M., Fathman C. G., Inaba K., Steinman R. M. Presentation of exogenous protein antigens by dendritic cells to T cell clones. Intact protein is presented best by immature, epidermal Langerhans cells. J Exp Med. 1989 Mar 1;169(3):1169–1178. doi: 10.1084/jem.169.3.1169. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Rudensky AYu, Preston-Hurlburt P., Hong S. C., Barlow A., Janeway C. A., Jr Sequence analysis of peptides bound to MHC class II molecules. Nature. 1991 Oct 17;353(6345):622–627. doi: 10.1038/353622a0. [DOI] [PubMed] [Google Scholar]
  30. Shimonkevitz R., Kappler J., Marrack P., Grey H. Antigen recognition by H-2-restricted T cells. I. Cell-free antigen processing. J Exp Med. 1983 Aug 1;158(2):303–316. doi: 10.1084/jem.158.2.303. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Steinman R. M., Cohn Z. A. The interaction of particulate horseradish peroxidase (HRP)-anti HRP immune complexes with mouse peritoneal macrophages in vitro. J Cell Biol. 1972 Dec;55(3):616–634. doi: 10.1083/jcb.55.3.616. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Steinman R. M., Cohn Z. A. The interaction of soluble horseradish peroxidase with mouse peritoneal macrophages in vitro. J Cell Biol. 1972 Oct;55(1):186–204. doi: 10.1083/jcb.55.1.186. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Steinman R. M. The dendritic cell system and its role in immunogenicity. Annu Rev Immunol. 1991;9:271–296. doi: 10.1146/annurev.iy.09.040191.001415. [DOI] [PubMed] [Google Scholar]
  34. Stössel H., Koch F., Kämpgen E., Stöger P., Lenz A., Heufler C., Romani N., Schuler G. Disappearance of certain acidic organelles (endosomes and Langerhans cell granules) accompanies loss of antigen processing capacity upon culture of epidermal Langerhans cells. J Exp Med. 1990 Nov 1;172(5):1471–1482. doi: 10.1084/jem.172.5.1471. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Ziegler H. K., Unanue E. R. Decrease in macrophage antigen catabolism caused by ammonia and chloroquine is associated with inhibition of antigen presentation to T cells. Proc Natl Acad Sci U S A. 1982 Jan;79(1):175–178. doi: 10.1073/pnas.79.1.175. [DOI] [PMC free article] [PubMed] [Google Scholar]

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