Skip to main content
PMC home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1978 Apr 1;147(4):1175–1188. doi: 10.1084/jem.147.4.1175

Bacille Calmette-Guerin infection in the mouse. Regulation of macrophage plasminogen activator by T lymphocytes and specific antigen

PMCID: PMC2184256  PMID: 349108

Abstract

High levels of plasminogen activator (PA) were induced in mouse peritoneal macrophages by infection with BCG, 2-6 X 10(7) viable organisms intravenously, followed 3-4 wk later by intraperitoneal challenge with purified protein derivative (PPD) 2 days before harvest. Macrophages obtained from infected animal without boosting showed little fibrinolytic activity, but challenge of Bacille-Calmette-Guerin (BCG)-primed peritoneal cells with PPD in culture also enhanced macrophage PA 4- to 10-fold. Stimulation of macrophage PA by PPD depended on specifically sensitized thymus-derived (T) lymphocytes because it was abolished by pretreatment of BCG-primed peritoneal cells with anti-thy 1.2 antiserum and complement. A direct assay was developed in which nylon wool separated sensitized lymphocytes and PPD induced PA in macrophages from uninfected animals under defined conditions on 125I-fibrin. Enhanced macrophage fibrinolysis was proportional to concentration of PPD and the number of sensitized lymphocytes transferred. An indirect two-stage assay was also used to show that BCG-sensitized peritoneal cells released a soluble inducer of macrophage PA into the culture medium, after challenge with PPD. Induction of macrophage PA by PPD challenge in vitro made it possible to study the generation and activity of sensitized peritoneal lymphocytes at different stages of infection. Our results show that nonadherent peritoneal cells of BCG-infected mice provide a rich source of specifically sensitized lymphocytes and that macrophage activation is limited by continued availability of antigen, as well as sensitized lymphocytes. Induction of macrophage PA provides a sensitive, versatile, and rapid in vitro assay to study the role of lymphocytes and specific antigen in macrophage activation by BCG.

Full Text

The Full Text of this article is available as a PDF (866.4 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. ARNASON B. G., JANKOVIC B. D., WAKSMAN B. H., WENNERSTEN C. Role of the thymus in immune reactions in rats. II. Suppressive effect of thymectomy at birth on reactions of delayed (cellular) hypersensitivity and the circulating small lymphocyte. J Exp Med. 1962 Aug 1;116:177–186. doi: 10.1084/jem.116.2.177. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Armstrong J. A., Hart P. D. Response of cultured macrophages to Mycobacterium tuberculosis, with observations on fusion of lysosomes with phagosomes. J Exp Med. 1971 Sep 1;134(3 Pt 1):713–740. doi: 10.1084/jem.134.3.713. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bianco C., Eden A., Cohn Z. A. The induction of macrophage spreading: role of coagulation factors and the complement system. J Exp Med. 1976 Dec 1;144(6):1531–1544. doi: 10.1084/jem.144.6.1531. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Blanden R. V., Lefford M. J., Mackaness G. B. The host response to Calmette-Guérin bacillus infection in mice. J Exp Med. 1969 May 1;129(5):1079–1107. doi: 10.1084/jem.129.5.1079. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Chao P., Francis L., Atkins E. The release of an endogenous pyrogen from guinea pig leukocytes in vitro: a new model for investigating the role of lymphocytes in fevers induced by antigen in hosts with delayed hypersensitivity. J Exp Med. 1977 May 1;145(5):1288–1298. doi: 10.1084/jem.145.5.1288. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Chase M. W., Kawata H. Multiple mycobacterial antigens in diagnostic tuberculins. Dev Biol Stand. 1975;29:308–330. [PubMed] [Google Scholar]
  7. Deutsch D. G., Mertz E. T. Plasminogen: purification from human plasma by affinity chromatography. Science. 1970 Dec 4;170(3962):1095–1096. doi: 10.1126/science.170.3962.1095. [DOI] [PubMed] [Google Scholar]
  8. Galindo B., Lazdins J., Castillo R. Fusion of normal rabbit alveolar macrophages induced by supernatant fluids from BCG-sensitized lymph node cells after elicitation by antigen. Infect Immun. 1974 Feb;9(2):212–216. doi: 10.1128/iai.9.2.212-216.1974. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Gordon S., Todd J., Cohn Z. A. In vitro synthesis and secretion of lysozyme by mononuclear phagocytes. J Exp Med. 1974 May 1;139(5):1228–1248. doi: 10.1084/jem.139.5.1228. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Gordon S., Unkeless J. C., Cohn Z. A. Induction of macrophage plasminogen activator by endotoxin stimulation and phagocytosis: evidence for a two-stage process. J Exp Med. 1974 Oct 1;140(4):995–1010. doi: 10.1084/jem.140.4.995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. 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]
  12. Klimetzek V., Sorg C. Lymphokine-induced secretion of plasminogen activator by murine macrophages. Eur J Immunol. 1977 Mar;7(3):185–187. doi: 10.1002/eji.1830070314. [DOI] [PubMed] [Google Scholar]
  13. Lagrange P. H., Mackaness G. B. A stable form of delayed-type hypersensitivity. J Exp Med. 1975 Jan 1;141(1):82–96. doi: 10.1084/jem.141.1.82. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Lagrange P. H., Mackaness G. B., Miller T. E. Influence of dose and route of antigen injection on the immunological induction of T cells. J Exp Med. 1974 Mar 1;139(3):528–542. doi: 10.1084/jem.139.3.528. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Lane F. C., Unanue E. R. Requirement of thymus (T) lymphocytes for resistance to listeriosis. J Exp Med. 1972 May 1;135(5):1104–1112. doi: 10.1084/jem.135.5.1104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Lefford M. J., McGregor D. D., Mackaness G. B. Immune response to Mycobacterium tuberculosis in rats. Infect Immun. 1973 Aug;8(2):182–189. doi: 10.1128/iai.8.2.182-189.1973. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Lefford M. J., McGregor D. D., Mackaness G. B. Properties of lymphocytes which confer adoptive immunity to tuberculosis in rats. Immunology. 1973 Oct;25(4):703–715. [PMC free article] [PubMed] [Google Scholar]
  18. Lefford M. J. Transfer of adoptive immunity to tuberculosis in mice. Infect Immun. 1975 Jun;11(6):1174–1181. doi: 10.1128/iai.11.6.1174-1181.1975. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Littman B. H., Ruddy S. Production of the second component of complement by human monocytes: stimulation by antigen-activated lymphocytes or lymphokines. J Exp Med. 1977 May 1;145(5):1344–1352. doi: 10.1084/jem.145.5.1344. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Mackaness G. B., Auclair D. J., Lagrange P. H. Immunopotentiation with BCG. I. Immune response to different strains and preparations. J Natl Cancer Inst. 1973 Nov;51(5):1655–1667. doi: 10.1093/jnci/51.5.1655. [DOI] [PubMed] [Google Scholar]
  21. Nogueira N., Gordon S., Cohn Z. Trypanosoma cruzi: modification of macrophage function during infection. J Exp Med. 1977 Jul 1;146(1):157–171. doi: 10.1084/jem.146.1.157. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Nogueira N., Gordon S., Cohn Z. Trypanosoma cruzi: the immunological induction of macrophage plasminogen activator requires thymus-derived lymphocytes. J Exp Med. 1977 Jul 1;146(1):172–183. doi: 10.1084/jem.146.1.172. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. North R. J. Importance of thymus-derived lymphocytes in cell-mediated immunity to infection. Cell Immunol. 1973 Apr;7(1):166–176. doi: 10.1016/0008-8749(73)90193-7. [DOI] [PubMed] [Google Scholar]
  24. North R. J. T cell dependence of macrophage activation and mobilization during infection with Mycobacterium tuberculosis. Infect Immun. 1974 Jul;10(1):66–71. doi: 10.1128/iai.10.1.66-71.1974. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. OLD L. J., BENACERRAF B., CLARKE D. A., CARSWELL E. A., STOCKERT E. The role of the reticuloendothelial system in the host reaction to neoplasia. Cancer Res. 1961 Oct;21:1281–1300. [PubMed] [Google Scholar]
  26. Roblin R. O., Hammond M. E., Bensky N. D., Dvorak A. M., Dvorak H. F., Black P. H. Generation of macrophage migration inhibitory activity by plasminogen activators. Proc Natl Acad Sci U S A. 1977 Apr;74(4):1570–1574. doi: 10.1073/pnas.74.4.1570. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Takeya K., Mori R., Nomoto K., Nakayama H. Experimental mycobacterial infections in neonatally thymectomized mice. Am Rev Respir Dis. 1967 Sep;96(3):469–477. doi: 10.1164/arrd.1967.96.3.469. [DOI] [PubMed] [Google Scholar]
  28. Unkeless J. C., Gordon S., Reich E. Secretion of plasminogen activator by stimulated macrophages. J Exp Med. 1974 Apr 1;139(4):834–850. doi: 10.1084/jem.139.4.834. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Vassalli J. D., Reich E. Macrophage plasminogen activator: induction by products of activated lymphoid cells. J Exp Med. 1977 Feb 1;145(2):429–437. doi: 10.1084/jem.145.2.429. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Wahl L. M., Wahl S. M., Mergenhagen S. E., Martin G. R. Collagenase production by lymphokine-activated macrophages. Science. 1975 Jan 24;187(4173):261–263. doi: 10.1126/science.163038. [DOI] [PubMed] [Google Scholar]
  31. Wahl S. M., Wilton J. M., Rosenstreich D. L., Oppenheim J. J. The role of macrophages in the production of lymphokines by T and B lymphocytes. J Immunol. 1975 Apr;114(4):1296–1301. [PubMed] [Google Scholar]
  32. Werb Z., Gordon S. Elastase secretion by stimulated macrophages. Characterization and regulation. J Exp Med. 1975 Aug 1;142(2):361–377. doi: 10.1084/jem.142.2.361. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Werb Z., Gordon S. Secretion of a specific collagenase by stimulated macrophages. J Exp Med. 1975 Aug 1;142(2):346–360. doi: 10.1084/jem.142.2.346. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES