Springer Seminars in Immunopathology

, Volume 10, Issue 4, pp 337–358 | Cite as

The role of T cell — Macrophage interactions in tuberculosis

  • Stefan H. E. Kaufmann
  • Inge E. A. Flesch


Acquired resistance against tuberculosis paradigmatically depends on specific T lymphocytes and mononuclear phagocytes. The etiological agent,Mycobacterium tuberculosis is capable of replicating in mononuclear phagocytes which act both as habitat and as effectors of protection. Upon interaction with antigen-specific T lymphocytes infected mononuclear phagocytes acquire tuberculosis activities. Here, data from experimental tuberculosis studies in mice are summarized which show that: interleukins produced by cloned T cells and recombinant interferon-γ are capable of activating tuberculostatic capacities in macrophages; both CD4 and CD8 T cells, after adequate stimulation, produce interferon-γ; CD8 T cells lyse macrophages in an antigen-specific way; not only CD8 but also CD4 T cells possess an antigen-specific cytolytic potential; lysis of infected macrophages results in mycobacterial growth inhibition. Evidence is also presented that tuberculostatic activities of activated macrophages depend on phagosome-lysosome fusion and are independent of reactive oxygen metabolites and that some strains ofM. tuberculosis are resistant against interferon-γ activated macrophages. These findings suggest that both helper and cytolytic T cells participate in the immune response to tuberculosis and that similar T cell mechanisms contribute to resistance as well as pathogenesis. Protection against tuberculosis, therefore, depends on subtle coordination of the immune response.


Immune Response Tuberculosis Mycobacterium Tuberculosis Etiological Agent Tuberculosis Activity 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Adams DO, Hamilton TA (1984) The cell biology of macrophage activation. Ann Rev Immunol 2: 283Google Scholar
  2. 2.
    Adams JS, Gacad ME (1985) Characterization of 1α-hydroxylation of vitamin D3 sterols by cultured alveolar macrophages from patients with sarcoidosis. J Exp Med 161: 755PubMedGoogle Scholar
  3. 3.
    Andrew PW, Rees ADM, Scoging A, Dobson N, Matthews R, Whittall JT, Coates ARM, Lowrie DB (1984) Secretion of a macrophage-activating factor distinct from interferon-γ by human T cell clones. Eur J Immunol 14: 962PubMedGoogle Scholar
  4. 4.
    Beck JS, Morley SM, Gibbs JH, Potts RC, Ilias MI, Kardjito T, Grange JM, Stanford J, Brown RA (1986) The cellular responses of tuberculosis and leprosy patients and of healthy controls in skin tests to “New Tuberculin” and Leprosin A. Clin Exp Immunol 64: 484PubMedGoogle Scholar
  5. 5.
    Bishop DK, Hinrichs DJ (1987) Adoptive transfer of immunity toListeria monocytogenes. The influence of in vitro stimulation on lymphocyte subset requirements. J Immunol 139: 2005PubMedGoogle Scholar
  6. 6.
    Bloom BR, Bennet B (1966) Mechanism of a reaction in vitro associated with delayed-type hypersensitivity. Science 153: 80PubMedGoogle Scholar
  7. 7.
    Chase MW (1945) The cellular transfer of cutaneous hypersensitivity to tuberculin. Proc Soc Exp Biol Med 59: 134Google Scholar
  8. 8.
    Chiplunkar S, De Libero G, Kaufmann SHE (1986)Mycobacterium leprae-specific Lyt2+ T lymphocytes with cytolytic activity. Infect Immun 54: 793PubMedGoogle Scholar
  9. 9.
    Clark SC, Kamen R (1987) The human hematopoietic colony-stimulating factors. Science 236: 1229PubMedGoogle Scholar
  10. 10.
    Cobbold SP, Jayasuriy A, Nash A, Prospero TD, Waldmann H (1984) Therapy with monoclonal antibodies by elimination of T cell subsets in vivo. Nature 312: 548PubMedGoogle Scholar
  11. 11.
    Cohen MS, Mesler DE, Snipes RG, Gray TK (1986) 1,25-Dihydroxyvitamin D3 activates secretion of hydrogen peroxide by human monocytes. J Immunol 136: 1049PubMedGoogle Scholar
  12. 12.
    Crawford RM, Finbloom DS, Ohara J, Paul WE, Meltzer MS (1987) B cell stimulatory factor-1 (interleukin 4) activates macrophages for increased tumoricidal activity and expression of Ia antigens. J Immunol 139: 135PubMedGoogle Scholar
  13. 13.
    Crowle AJ, Ross EJ, May MH (1987) Inhibition by 1,25(OH)2-vitamin D3 of the multiplication of virulent tubercle bacilli in cultured human macrophages. Infect Immun 55: 2945PubMedGoogle Scholar
  14. 14.
    Czuprynski CJ, Brown JF (1987) Dual regulation of antibacterial resistance and inflammatory neutrophil and macrophage accumulation by L3T4+ and Lyt2+ Listeria-immune T cells. Immunology 60: 287PubMedGoogle Scholar
  15. 15.
    David JR (1966) Delayed-hypersensitivity in vitro: its mediation by cell free substances formed by lymphoid cell antigen interaction. Proc Natl Acad Sci USA 56: 72PubMedGoogle Scholar
  16. 16.
    De Libero G, Flesch I, Kaufmann SHE (1988) Mycobacteria-reactive Lyt2+ T cell lines. Eur J Immunol 18: 59PubMedGoogle Scholar
  17. 17.
    Esparza I, Männel D, Ruppel A, Falk W, Krammer PH (1987) Interferon-γ and lymphotoxin or tumor necrosis factor act synergistically to induce macrophage killing of tumor cells and schistosomula ofSchistosoma mansoni. J Exp Med 166: 589PubMedGoogle Scholar
  18. 18.
    Feinman R, Hendriksen-De Stefano D, Tsujimoto M, Vilcek J (1987) Tumor necrosis factor is an important mediator of tumor cell killing by human monocytes. J Immunol 138: 635PubMedGoogle Scholar
  19. 19.
    Fitch FW (1986) T cell clones and T cell receptors. Microbiol Rev 50: 50PubMedGoogle Scholar
  20. 20.
    Flesch I, Ferber E (1986) Growth requirements of murine bone marrow macrophages in serum-free cell culture. Immunobiology 171: 14PubMedGoogle Scholar
  21. 21.
    Flesch I, Ferber E (1986) Effect of cellular fatty acid composition on the phospholipase A2 activity of bone marrow-derived macrophages, and their ability to induce lucigenin-dependent chemiluminescence. Biochim Biophys Acta 889: 6PubMedGoogle Scholar
  22. 22.
    Flesch I, Kaufmann SHE (1987) Mycobacterial growth inhibition by interferon-γ-activated bone marrow macrophages and differential susceptibility among strains ofMycobacterium tuberculosis. J Immunol 138: 4408PubMedGoogle Scholar
  23. 23.
    Flesch IEA, Kaufmann SHE (1988) Attempts to characterize the mechanisms involved in mycobacterial growth inhibition by interferon-γ-activated bone marrow macrophages. Infect Immun 56: 1464PubMedGoogle Scholar
  24. 24.
    Flesch I, Früh A, Ferber E (1986) Functional comparison of bone marrow-derived macrophages obtained by cultivation in serum-free or serum-supplemented medium. Immunobiology 173: 72PubMedGoogle Scholar
  25. 25.
    Germain RN (1986) The ins and outs of antigen processing and presentation. Nature 322: 687PubMedGoogle Scholar
  26. 26.
    Gluck WL, Weinberg JB (1987) 1α,25-Dihydroxyvitamin D3 and mononuclear phagocytes: enhancement of mouse macrophage and human monocyte hydrogen peroxide production without alteration of tumor cytolysis. J Leukocyte Biol 42: 498PubMedGoogle Scholar
  27. 27.
    Goddeeris BM, Morrison WI, Teale AJ, Bensaid A, Baldwin CL (1986) Bovine cytotoxic T cell clones specific for cells infected with the protozoan parasiteTheileria parva: parasite strain specificity and class I major histocompatibility complex restriction. Proc Natl Adac Sci USA 83: 5238Google Scholar
  28. 28.
    Grange JM (1985) Virulence ofMycobacterium tuberculosis. FEMS Microbiol Rev 32: 44Google Scholar
  29. 29.
    Hahn H, Kaufmann SHE (1982) Role of cell-mediated immunity in bacterial infections. Rev Infect Dis 3: 1221Google Scholar
  30. 30.
    Hamilton TA, Rigsbee YE, Scott WA, Adams DO (1985) Gamma-interferon enhances the secretion of arachidonic acid metabolites from murine peritoneal macrophages stimulated with phorbol diesters. J Immunol 134: 2631PubMedGoogle Scholar
  31. 31.
    Hart P D'Arcy, Young MR (1978) Manipulations of the phagosome-lysosome fusion response in cultured macrophages. Enhancement of fusion by chloroquine and other amines. Exp Cell Res 114: 486PubMedGoogle Scholar
  32. 32.
    Hart P D'Arcy, Young MR, Gordon AH, Sullivan KH (1987) Inhibition of phagosome-lysosome fusion in macrophage by certain mycobacteria can be explained by inhibition of lysosomal movements observed after phagocytosis. J Exp Med 166: 933PubMedGoogle Scholar
  33. 33.
    Hussein S, Curtis J, Griffiths D, Turk JL (1987) Study of DTH and resistance inMycobacterium lepraemurium infection using a T cell line isolated from mice infected withMycobacterium bovis (BCG). Cell Immunol 105: 423PubMedGoogle Scholar
  34. 34.
    Jackett PS, Aber VR, Mitchison DA, Lowrie DB (1981) The contribution of hydrogen peroxide resistance toMycobacterium tuberculosis during the first six days after intravenous infection of normal and BCG-vaccinated guinea-pigs. Br J Exp Pathol 62: 34PubMedGoogle Scholar
  35. 35.
    Jackett PS, Andrew PW, Aber VR, Lowrie DB (1983) Guinea pig alveolar macrophages probably killM. tuberculosis H37Rv and H37Ra in vivo by producing hydrogen peroxide. Adv Exp Med Biol 162: 99PubMedGoogle Scholar
  36. 36.
    Kaufmann SHE (1987) Towards new leprosy and tuberculosis vaccines. Microbiol Sci 4: 324PubMedGoogle Scholar
  37. 37.
    Kaufmann SHE, Flesch I (1986) Function and antigen recognition pattern of L3T4+ T cell clones fromMycobacterium tuberculosis-immune mice. Infect Immun 54: 291PubMedGoogle Scholar
  38. 38.
    Kaufmann SHE, Simon MM, Hahn H (1979) Specific Lyt 123 T cells are involved in protection againstListeria monocytogenes and in delayed-type hypersensitivity to listerial antigens. J Exp Med 150: 1033PubMedGoogle Scholar
  39. 39.
    Kaufmann SHE, Hug E, Väth U, Müller I (1985) Effective protection againstListeria monocytogenes and delayed-type hypersensitivity to listerial antigens depend on cooperation between specific L3T4+ and Lyt2+ T cells. Infect Immun 48: 263PubMedGoogle Scholar
  40. 40.
    Kaufmann SHE, Hug E, De Libero G (1986)Listeria monocytogenes-reactive T lymphocyte clones with cytolytic activity against infected target cells. J Exp Med 164: 363PubMedGoogle Scholar
  41. 41.
    Kaufmann SHE, Hug E, Väth U, De Libero G (1987) Specific lysis ofListeria monocytogenes-infected macrophages by class II-restricted L3T4+ T cells. Eur J Immunol 17: 237PubMedGoogle Scholar
  42. 42.
    Kaufmann SHE, Väth U, Thole JER, Van Embden JDA, Emmrich F (1987) Enumeration of T cells reactive withMycobacterium tuberculosis organisms and specific for the recombinant mycobacterial 64-kDa protein. Eur J Immunol 17: 351PubMedGoogle Scholar
  43. 43.
    Kishimoto T, Hirano T (1988) Molecular regulation of B lymphocyte response. Annu Rev Immunol 6: 485PubMedGoogle Scholar
  44. 44.
    Klebanoff SJ, Hamon CB Antimicrobial systems of mononuclear phagocytes. In: van Furth R (ed) Mononuclear phagocytes in immunity, infection and pathology. Blackwell, 1975, pp 507–529Google Scholar
  45. 45.
    Koch R (1882) Die Aetiologie der Tuberculose. Berl Klin Wochenschr 15: 221Google Scholar
  46. 46.
    Koch R (1890) Weitere Mitteilungen über ein Heilmittel gegen Tuberculose. Dtsch Med Wochenschr 46a: 3Google Scholar
  47. 47.
    Koeffler HP, Reichel H, Bishop JE, Norman AW (1985) γ-Interferon stimulates production of 1,25 dihydroxyvitamin D3 by normal human macrophages. Biochem Biophys Res Commun 127: 596PubMedGoogle Scholar
  48. 48.
    Kröner EE, Peskar BA, Fischer H, Ferber E (1980) Control of archidonic acid accumulation in bone marrow-derived macrophages by acyltransferase. J Biol Chem 256: 3690Google Scholar
  49. 49.
    Le J, Vilcek J (1987) Biology of disease. Tumor necrosis factor and interleukin 1: cytokines with multiple overlapping biological activities. Lab Invest 56: 234PubMedGoogle Scholar
  50. 50.
    Lemire JM, Adams JS, Kermani-Arab V, Bakke AC, Sakai R, Jordan SC (1986) 1,25-Dihydroxyvitamin D3 suppresses human T helper/inducer lymphocyte activity in vitro. J Immunol 134: 3032Google Scholar
  51. 51.
    Loeffler F (1890) Die bisherigen Veröffentlichungen über die Anwendung des Koch'schen Heilmittels gegen Tuberculose. Zentralbl Bakteriol Parasitenkd 8: 749Google Scholar
  52. 52.
    Lurie MB (1964) Resistance to tuberculosis: experimental studies in native and acquired defensive mechanisms. Harvard University Press, Cambridge, pp 1–391Google Scholar
  53. 53.
    Mackaness GB (1970) The monocyte in cellular immunology. Semin Hematol 7: 172PubMedGoogle Scholar
  54. 54.
    Meltzer MS, Benjamin WR, Farrar JJ (1982) Macrophage activation for tumor cytotoxicity: induction of macrophage tumoricidal activity by lymphokines from EL-4, a continuous T cell line. J Immunol 129: 2802PubMedGoogle Scholar
  55. 55.
    Metschnikoff E (1904) Die Lehre von den Phagocyten und deren experimentelle Grundlagen. In: Kolle W, Wassermann A (eds) Handbuch der pathogenen Mikroorganismen. Fischer, Jena pp 332–407Google Scholar
  56. 56.
    Modlin RL, Melancon-Kaplan J, Pirmez C, Young SMM, Kino H, Convit J, Rea TH, Bloom BR (1988) Learning from lesions: patterns of tissue inflammation in leprosy. Proc Natl Acad Sci USA 85: 1213PubMedGoogle Scholar
  57. 57.
    Mogil RJ, Patton CL, Green DR (1987) Cellular subsets involved in cell-mediated immunity to murinePlasmodium yoelii 17X malaria. J Immunol 138: 1933PubMedGoogle Scholar
  58. 58.
    Moulder JW (1985) Comparative biology of intracellular parasitism. Microbiol Rev 49: 298PubMedGoogle Scholar
  59. 59.
    Müller I, Cobbold SP, Waldmann H, Kaufmann SHE (1987) Impaired resistance againstMycobacterium tuberculosis infection after selective in-vivo depletion of L3T4+ and Lyt2+ T cells. Infect Immun 55: 2037PubMedGoogle Scholar
  60. 60.
    Myrvik QN, Leake ES, Wright MJ (1984) Disruption of phagosomal membranes of normal alveolar macrophages by the H37Rv strain ofMycobacterium tuberculosis. Am Rev Respir Dis 129: 322PubMedGoogle Scholar
  61. 61.
    Nacy CA, James SL, Benjamin WR, Farrar JJ, Hockmeyer WT, Meltzer MS (1983) Activation of macrophages for microbicidal and tumoricidal effector functions by soluble factors from EL-4, a continuous T cell line. Infect Immun 40: 820PubMedGoogle Scholar
  62. 62.
    Orme JM (1987) The kinetics of emergence and loss of mediator T lymphocytes acquired in response to infection withMycobacterium tuberculosis. J Immunol 138: 293PubMedGoogle Scholar
  63. 63.
    Orme IM, Collins FM (1984) Adoptive protection of theMycobacterium tuberculosis-infected lung. Dissociation between cells that passively transfer protective immunity and those that transfer delayed-type hypersensitivity to tuberculin. Cell Immunol 84: 113PubMedGoogle Scholar
  64. 64.
    Paul WE, Ohara J (1987) B-cell stimulatory factor-1/interleukin 4. Annu Rev Immunol 5: 429PubMedGoogle Scholar
  65. 65.
    Pavlov H, Hogarth M, McKenzie IFC, Cheers C (1982) In vivo and in vitro effects of monoclonal antibody to Ly antigens on immunity to infection. Cell Immunol 71: 127PubMedGoogle Scholar
  66. 66.
    Pedrazzini T, Hug K, Louis JA (1987) Importance of L3T4+ and Lyt2+ cells in the immunologic control of infection withMycobacterium bovis strain Bacillus Calmette Guerin in mice. Assessment by elimination of T cell subsets in vivo. J Immunol 139: 2032PubMedGoogle Scholar
  67. 67.
    Reed SG, Nathan CF, Pihl DL, Rodricks P, Shanebeck K, Conlon PJ, Grabstein KH (1987) Recombinant granulocyte/macrophage colony-stimulating factor activates macrophages to inhibitTrypanosoma cruzi and release hydrogen peroxide. J Exp Med 166: 1734PubMedGoogle Scholar
  68. 68.
    Reichel H, Koeffler HP, Tobler A, Norman AW (1987) 1,25-Dihydroxyvitamin D3 inhibits γ-interferon synthesis by normal human peripheral blood lymphocytes. Proc Natl Acad Sci USA 84: 3385PubMedGoogle Scholar
  69. 69.
    Rollwagen FM, Dasch GA, Jerrells TR (1986) Mechanisms of immunity to rickettsial infection: characterization of a cytotoxic effector cell. J Immunol 136: 1418PubMedGoogle Scholar
  70. 70.
    Rook GAW, Steele J, Fraher L, Barker S, Karmali R, O'Riordan J (1986) Vitamin D3, gamma interferon, and control of proliferation ofMycobacterium tuberculosis by human monocytes. Immunology 57: 159PubMedGoogle Scholar
  71. 71.
    Rook GAW, Taverne J, Leveton C, Steele J (1987) The role of gamma-interferon, vitamin D3 metabolites and tumor necrosis factor in the pathogenesis of tuberculosis. Immunology 62: 229PubMedGoogle Scholar
  72. 72.
    Schofield L, Villaquiran J, Ferreira A, Schellekens H, Nussenzweig R, Nussenzweig V (1987) γ-interferon, CD8+ T cells and antibodies required for immunity to malaria sporozoites. Nature 330: 664PubMedGoogle Scholar
  73. 73.
    Shapiro ME, Onderdonk AB, Kasper DL, Finberg RW (1982) Cellular immunity toBacteroides fragilis capsular polysaccharide. J Exp Med 154: 1188Google Scholar
  74. 74.
    Smith K (1984) Interleukin 2. Annu Rev Immunol 2: 319PubMedGoogle Scholar
  75. 75.
    Takatsu K, Kikuchi Y, Takahashi T, Honjo T, Matsumoto M, Harada N, Yamaguchi N, Tominaga A (1987) Interleukin 5, a T cell-derived B cell differentiation factor also induces cytotoxic T lymphocytes. Proc Natl Acad Sci USA 84: 4234PubMedGoogle Scholar
  76. 76.
    Titus RG, Milon G, Marchal G, Vassalli P, Cerottini JC, Louis JA (1987) Involvement of specific Lyt-2+ T cells in the immunological control of experimentally induced murine cutaneous leishmaniasis. Eur J Immunol 17: 1429PubMedGoogle Scholar
  77. 77.
    Turner RT, Bottemiller BL, Howard GA, Baylink DJ (1980) In vitro metabolism of 25-hydroxyvitamin D3 by isolated rat kidney cells. Proc Natl Acad Sci USA 77: 1537PubMedGoogle Scholar
  78. 78.
    Vismara D, Lombardi G, Piccolella E, Colizzi V (1985) Dissociation between interleukin-1 and interleukin-2 production in proliferative response to microbial antigens: restorative effect of exogenous interleukin-2. Infect Immun 49: 298PubMedGoogle Scholar
  79. 79.
    Walker L, Lowrie DB (1981) Killing ofMycobacterium microti by immunologically activated macrophages. Nature 293: 69PubMedGoogle Scholar
  80. 80.
    Weiser WY, Van Niel A, Clark SC, David JR, Remold HG (1987) Recombinant human granulocyte/macrophage colony-stimulating factor activates intracellular killing ofLeishmania donovani by human monocyte-derived macrophages. J Exp Med 166: 1436PubMedGoogle Scholar
  81. 81.
    Weiss WR, Sedegah M, Beaudoin RL, Miller LH, Good MF (1988) CD8+ T cells (cytotoxic/suppressors) are required for protection in mice immunized with malaria sporozoites. Proc Natl Acad Sci USA 85: 573PubMedGoogle Scholar
  82. 82.
    Zlotnik A, Fischer M, Roehm N, Zipori D (1987) Evidence for effects of interleukin 4 (B cell stimulatory factor 1) on macrophages: enhancement of antigen presenting ability of bone marrow-derived macrophages. J Immunol 138: 4275PubMedGoogle Scholar

Copyright information

© Springer-Verlag New York, Inc. 1988

Authors and Affiliations

  • Stefan H. E. Kaufmann
    • 1
  • Inge E. A. Flesch
    • 1
  1. 1.Department of Medical Microbiology and ImmunologyUniversity of Ulm, Oberer EselsbergUlmFederal Republic of Germany

Personalised recommendations