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Are inflammatory phagocytes responsible for resistance to facultative intracellular bacteria?
Immunology Today, voL 7, No. 3, 1986
r--roslrum
Are inflammatory phagocytes responsible for resistance to facultative intracellular bacteria? At least 38 deaths from listeriosis in the United States in recent months have drawn attention to how tittle we know about resistance to facultative intracellular bacteria. Much more is known about resistance to obligate intracellular parasites. Macrophages, activated by T cell-derived macrophage activating factors (MAF), are able to kill obligate intracellular parasites and tumor cells1-1° including Leishmania, certain trypanosomes, Toxoplasma,the obligate intracellular bacterium Rickettsia, and perhaps bacteria such as mycobacteria and Legionella. However, macrophages, stimulated by MAF, may not be the only host cells which can defend against infection by facultative intracellular bacteria such as Salmonella typhimurium or Listeriamonocytogenes.Six different observations made by Priscilla Campbell and colleagues, and by others, suggest that it is not the so-called "activated' macrophage which is primarily responsible for resistance against facultative intracellular bacteria. Rather, she proposes that an early inflammatory cell recently recruited in response to an "Inflammatory stimulus - a cell whose presence seems to be under the control of immunologically-specific T cells - plays a critical role in resistance to infection by these organisms.
The first observation is that neutrophils kill Listeria, as well as Salmonella and E. coil, in vitro at least as efficiently as do mononuclear cells and macrophages in both mice and man 1I 14. As human peripheral blood mononuclear cells mature in vitro and acquire high levels of tumoricidal activity they lose bactericidal activity13'1s. The potential importance of neutrophils in combating infections by facultative intracellular bacteria was first noted by investigators who identified these inflammatory cells in early infectious lesions16-18. Thus, not only are peripheral blood monocytes and macrophages capable of killing facultative intracellular bacteria, but so are peripheral blood neutrophils in man, and inflammatory peritoneal exudate neutrophils in mice. Second, inflammatory peritoneal exudate neutrophils and macrophages, elicited with the inflammatory agent proteose peptone, kill listeria just as well as do antigen-elicited peritoneal exudate neutrophils and macrophages, elicited presumably by T cell-dependent mechanisms 14. Resident cells are not bactericidal. In these experiments it didn't matter whether peritoneal exudate cells were collected from nonimmunized mice injected only with an inflammatory agent or from hyperimmunized mice resistant to 100-1000 LDso of Listeria that had been injected with Listeria antigens. When the
70
Departmentof Medidne, NationalJewish Center;and Departmentsof Pathologyand Medicine, Universityof ColoradoHealth SciencesCenter, Denver, CO80206, USA O 1986, ElsevierSciencePublishers B.V., Amsterdam 0167 4919/86/$02.00
Priscilla A. Campbell ability of these cells to kill Listeria was titrated, all cell populations killed equally. The hyperimmunized animals did differ, however, in the number of cells recruited to the peritoneal cavity in response to challenge with injected Listeria antigens: immunized mice recruited more neutrophils and macrophages than did nonimmunized mice. Miyata et a/.l~have also reported enhanced accumulation of peritoneal macrophages in immune mice challenged with Listeria antigens. This suggests that a critical event in developing resistance to these bacteria is the elicitation of an inflammatory response which results in recruitment of an increased number of cells which are capable of killing bacteria, rather than activation of phagocytes to higher levels of bactericidal activity. The third observation is that immune spleen T cells which transfer resistance to Listeria from immune mice to normal mice also transfer the ability to recruit inflammatory cells2°. Transfer of resistance and of an inflammatory response requires T cells and antigenic stimulation, and is dependent on the number of cells injected. Mice injected intraperitoneally with immune T cells recruited more macrophages and neutrophils to the peritoneal cavity after challenge with Listeria antigen than did mice injected with nonimmune T cells. But the phagocytes which were recruited in the presence of immune versus nonimmune T cells killed Listeria equally well. As before, macrophages and neutrophils which accumulated in the presence of immune T cells were no better at killing Listeria than phagocytes elicited in the presence of normal T cells; in the presence of immune T cells, more phagocytes were recruited. The fourth line of evidence implicating inflammatory cells in resistance to infection by facultative intracellular bacteria is derived from studies in genetically-resistant versus genetically-susceptible mice. The major defect in mice which are genetically-susceptible to listeriosis is in their ability to recruit cells to the peritoneal cavity when challenged with Listeria antigens or inflammatory agents 21 24 . C57BI/6 mice, which are resistant to Listeria, recruit more neutrophils at 4 h and macrophages at 48 h in response to Listeria challenge or challenge with an inflammatory agent than do A/J mice, which are susceptible to Listeria 21-23. Moreover, most strains of mice which are sensitive to Listeria are C5-deficient, while most strains of mice which are resistant to Listeria have normal
Immunology Today, voL Z No. 3, 1986
levels of C5 (Refs 21 and 22). When one attempts to reconstitute C5 levels in C5-deficient mice by injecting normal plasma, there is an increase in survival of the sensitive mice in response to Listeria and there is an increase in their ability to recruit inflammatory cells 22'23. These data again suggest that a defect in the ability of mice to recruit inflammatory cells effectively, perhaps because of a deficiency in complement-derived chemotactic factors, is primarily responsible for genetic susceptibility to Listeria. The fifth observation is that activation of macrophages to express tumoricidal activity does not necessarily result in expression of bactericidal activity. It was shown by Wing and Remington that macrophages from Trichinella- or Toxoplasmainfected mice differed in their abilities to kill tumor cells and intracetlular parasites depending on the time of in-vitro macrophage cultivation6'2~ Nacy et a/. were able to dissociate tumoricidal activity from the ability of macrophages to limit intracellular growth of Rickettsia by using different lymphokine fractions in vitro 7. Hopper and Cahil126 showed that macrophages with bactericidal activity were distinguished from those with tumoricidal activity by kinetics during secondary infection with Salmonella enteritidis, and by sedimentation velocity separation. We have shown that Bacille Calmette-Guerin (BCG) elicits peritoneal exudate macrophages which can kill tumor cells but which cannot kill Listeria or E. coil, although they are occasionally bacteriostatic for these organisms 27. On the other hand, peritoneal exudate macrophages elicited with proteose peptone are highly bactericidal but are unable to kill tumor cells. This has been demonstrated in both mice and hamsters, and using three different tumor targets 27. Thus it is possible to use selective stimuli to elicit populations of macrophages which express one activity but not the other. While there are many reports in the literature describing in-vivo and in-vitro stimuli which give rise to tumoricidal macrophages and there are several describing those stimuli which induce bactericidal capabilities, there are no reports as far as I am aware which demonstrate that a single population of cells can be induced to express both activities. Whether a single cell can express both tumoricidal and bactericidal capabilities, or not, remains to be shown. My colleagues and I find that peritoneal exudate macrophages from mice injected with BCG 2 weeks before harvest and with proteose peptone 2 days before harvest are both tumoricidal and bactericidal. But we have no evidence that the same cell is responsible for both activities, and suspect that it is not. Whether bactericidal and tumoricidal activities are dissociable because they are properties of macrophages at different stages of maturation, or because macrophages have been selectively induced to express a particular functional capacity by the stimuli they receive, or because of combinations of these and perhaps other unknown mechanisms, is not yet clear. The sixth line of evidence suggesting that the
rostrummacrophage activated to kill tumor cells may not be the cell exclusively responsible for killing facultative intracellular bacteria is derived from experiments using gamma interferon (IFN-~/)to stimulate macrophage function. Several laboratories have shown that IFN-~/, a T cell-derived lymphokine, can function as a macrophage activating factor which stimulates tumoricidal activity28-32. IFN-~/ has also been implicated as a lymphokine which stimulates macrophages to kill obligate intracellular parasites such as Leishmania, and Zoxoplasma 10'33. T-cell clones and hybrids which transfer resistance to listeriosis all secrete IFN-~ following antigenic challenge 34"3s. While there is evidence that recombinant IFN-T may participate in in-vivo induction of resistance against listeriosis36, evidence that it specifically triggers macrophages to express enhanced bactericidal activity is still lacking. In one recent report 37, monoclonal antibodies to IFN-~/ were reported to decrease the ability of a lymphokine preparation to slow growth of L. monocytogenes. But unfortunately the lymphokine preparation itself did not stimulate the macrophages to express either bactericidal or bacteriostatic activity. Rather in the presence of IFN-~/-containing supernatant, the bacterial population still quadrupled in 13 hours while in the absence of lymphokine it increased 18 times. IFN-~/ does not seem to activate macrophages to kill Listeria (P,A. Campbell, unpublished and S.H.E. Kaufmann, unpublished.). On the other hand, Douvas et a/. 38 showed that IFN-~/ stimulates human macrophages to become tumoricidal and leishmanicidal, but M. tuberculosis organisms grow better in these IFN-~-stimulated macrophages. Although a role for IFN-~/ in resistance against Listeria seems likely based on studies with Listeria-reactive T-cell clones, IFN-~/ does not seem to function by activating macrophages to express bactericidal activity. Its role in resistance to bacterial infection, if any, is yet to be clarified. My hypothesis is that early inflammatory phagocytes, cells recruited by antigen-specific T cells, are the primary mediators of resistance to infection by facultative intracellular bacteria. Whether T cells function by secreting lymphokines chemotactic for inflammatory cells, or perhaps by releasing agents which indirectly elicit inflammatory cells, is not yet known. The role of migration inhibition factor 39.40 • and IFN--y, T-cell products which have been implicated in resistance to listeriosis, is also not yet clear. Nevertheless, it seems that we should consider the hypothesis that T cells contribute significantly to resistance to infection by facultative intracellular bacteria, and perhaps by other organisms as well, by recruiting bactericidal inflammatory cells to the site of infection.
The authorthanks B. Canona,J. Cohen,J. Collins,J. Cook,A. Crowle, E. Goldson,P. Henson,K. Stedmanand W. Robertsfor critical review of the manuscript, and K. Crumrine and D. Thompson for secretarialassistance.
71
Immunology Today, vol. 7, No. 3, 1986
-rostrum References
1 Evans,R. and Alexander, P. (1972) Immunology 23, 615 2 Lohmann-Matthes, M.L, Ziegler, F.G and Fischer, H. (1973)
Eur. J. ImmunoL 3, 56 3 Piessens,W.F., Churchill, W.H. and David,J.R. (1975) J. ImmunoL 114, 293 4 Hibbs,J.B., Jr., Taintor, R.R.,Chapman, H.A., Jr. etaL (1977) Science 197, 279 5 Nogueira, N. and Cohn, Z.A. (1978)J. Exp. Med. 148, 288 6 Wing, E.J., KrahenbuhlJ.L. and Remington, J.S.(1979) Immunology 36,479 7 Nacy, C.A., Leonard, E.J.and Meltzer, MS. (1981) J. ImmunoL 126, 204 8 Walker, L. and Lowrie, D.B. (1981)Nature (London)293, 69 9 Murray, H.W., Byrne,G.I., Rothermel,C.D. etaL (1983) J. Exp, Med. 158, 234 10 Nathan, C.F., Murray, H.W., Wiebe, M.E. etaL (1983)J. Exp. Med. 158, 670 11 Steigbigel, R.T., Lambert, L.H., Jr. and Remington, J.S. (1974)J. Clin. Invest. 53,131 12 Peterson, P.K., Verhoef, J., Schmeling, D. etal. (1977) J. Infect. Dis. 136, 502 13 Czuprynski,CJ., Campbell, P.A. and Henson, P.M. (1983) J. ReticuloendotheL Soc. 34, 29 14 Czuprynski,C.J., Henson, P.M. and Campbell, P.A. (1984) J. Leukocyte Biol. 35, 193 15 Musson, R.A. (1983)Am. J. PathoL 111,331 16 Mackaness,G.B. (1962),/. Exp. Med. 116, 381 17 North R.J.(1970)J. Exp. Med. 132, 521 18 Mandel, T.E. and Cheers,C. (1980) Infect. Immun. 30, 851 19 Miyata, M., Mitsuyama, M., Ogata, N. etaL (1982) Immunology. 47, 247 20 Czuprynski,C.J., Henson, P.M. and Campbell, P.A. (1985) J. ImmunoL 134, 3449 21 Stevenson,M.M., Kongshavn, P.A. and Skamene, E. (1981)
J. Immunol. 127,402 22 Gervais,F., Stevenson,M and Skamene, E. (1984) J. Immunol. 132, 2078 23 Czuprynski, C.J., Canono, B.P., Henson, P.M. etaL (1985) Immunology. 55, 511 24 Kongshavn, P.A.L. Curr. Top. MicrobioL Immunol. (in press) 25 Wing, EJ., Gardner, I.D., Ryning, F.W. etal. (1977) Nature (London) 268, 642 26 Hopper, K.E. and Cahill, J.M (1983) J. ReticuloendotheL Soc. 33,443 27 Campbell, P.A., Czuprynski,C.J. and Cook, J.L (1984) J. Leukocyte Biol. 36, 293 28 Roberts,W.K. and Vasil,A. (1982)J. Interferon Res. 2, 519 29 Schultz, R.M and Kleinschmidt,WJ. (1983) Nature (London) 305,239 30 Pace,J.L., Russell,S.W., Schreiber, R.D. etaL (1983)Proc NatlAcad. Sci. USA 80, 3782 31 Pace,J.L, Russell,S.W., Torres, B.A. etaL (1983) J. ImmunoL 130, 2011 32 Spitalny, G.L. and Havell, E.A. (1984)J. Exp. Med. 159, 1560 33 Murray, H.W., Spitalny, G.L and Nathan, C.F. (1985) J. ImmunoL 134, 1619 34 Kaufmann, S.H.E.,Hahn, H., Berger, R. etal. (1983) Eur. J. ImmunoL 13,265 35 Kaufmann, S.H.E.(1985)in Monoclonal Antibodies Against Bacteria, Vol. I, pp. 233-267, Academic Press,New York 36 Kiderlen,A.F., Kaufmann, S.H.E.and Lohmann-Matthes, M.-L. (1984) Eur. J. Immunol. 14, 964 37 Schreiber, R.D., Hicks, LJ., Celada, A. etal. (1985) J. ImmunoL 134, 1609 38 Douvas,G.S., Looker, D.L., Vatter, A.E. etal. (1985) Infect. Immun. 50, 1 39 Kearns,R.J.and Campbell, P.A. (1983) Int. Arch. Allergy AppL Immunol. 70, 59 48 Sperling, U., Kaufmann, S.H.E.and Hahn, H. (1984)Infect. Immun. 46, 111
T-cell ontogeny: the role of a stimulator suppressor cell The thymus presents two major problems in cellular differentiation. How is self-non-self discrimination achieved in developing thymocytes? What determines the development of T-cell classes? In this discussion, Alan Herbert and James Watson propose a mechanism for regulating T-cell differentiation which involves the alternative pathway of T-cell activation. They postulate that T cells with a stimulator-suppressor phenotype stimulate resting helper T cells (Th) to produce interleukin 2 (IL-2) and suppress T cells which have bound antigen through antigenspedfic receptors by preventing induction of IL-2 receptors. Stimulator-suppressor T cells therefore suppress the donal expansion of T cells in an antigen-specific manner, yet promote their own clonal expansion in a manner independent of antigen. They further suggest that the molecule responsible for suppression is the product of the "1 genes known to rearrange in T cells. Human T cells bear three classes of cell surface receptors involved in activation: classical antigenbinding receptors which are distributed clonally on
72
Department of lmmunobiology, Universityof Auckland, PrivateBag Auckland, New Zealand (~) 1986, Elsevier Science Publishers B.V., Amsterdam
0167 -4919/86/$02.00
Alan G. Herbertand JamesD. Watson T ceils; a sheep erythrocyte-binding receptor present on all T cells; and the IL-2 receptor. Equivalents of these three types of receptor probably exist in T ceils of all mammalian species. In this article we will discuss mouse T lymphocytes and their development and will use the term 'E receptor' to describe the murine equivalent of the non-clonally specific structure which on human T cells binds sheep erythrocytes. T-cell activation usually occurs as a consequence of antigen-binding and leads to the expression of iL-2 receptors. Genes which encode antigen binding receptors have been identified in T cells by screening cDNA libraries for genes that are no longer in a germ line configuration. In each T cell, there are at least three genes which can undergo rearrangement, all of which have hydrophobic leader sequences 1 5 The ~ and 13 gene products combine to form ~13 heterodimers that participate in the MHC-restricted activation of T cells by antigen 6-8. The ~/ gene has limited diversity in its
r--roslrum
Are inflammatory phagocytes responsible for resistance to facultative intracellular bacteria? At least 38 deaths from listeriosis in the United States in recent months have drawn attention to how tittle we know about resistance to facultative intracellular bacteria. Much more is known about resistance to obligate intracellular parasites. Macrophages, activated by T cell-derived macrophage activating factors (MAF), are able to kill obligate intracellular parasites and tumor cells1-1° including Leishmania, certain trypanosomes, Toxoplasma,the obligate intracellular bacterium Rickettsia, and perhaps bacteria such as mycobacteria and Legionella. However, macrophages, stimulated by MAF, may not be the only host cells which can defend against infection by facultative intracellular bacteria such as Salmonella typhimurium or Listeriamonocytogenes.Six different observations made by Priscilla Campbell and colleagues, and by others, suggest that it is not the so-called "activated' macrophage which is primarily responsible for resistance against facultative intracellular bacteria. Rather, she proposes that an early inflammatory cell recently recruited in response to an "Inflammatory stimulus - a cell whose presence seems to be under the control of immunologically-specific T cells - plays a critical role in resistance to infection by these organisms.
The first observation is that neutrophils kill Listeria, as well as Salmonella and E. coil, in vitro at least as efficiently as do mononuclear cells and macrophages in both mice and man 1I 14. As human peripheral blood mononuclear cells mature in vitro and acquire high levels of tumoricidal activity they lose bactericidal activity13'1s. The potential importance of neutrophils in combating infections by facultative intracellular bacteria was first noted by investigators who identified these inflammatory cells in early infectious lesions16-18. Thus, not only are peripheral blood monocytes and macrophages capable of killing facultative intracellular bacteria, but so are peripheral blood neutrophils in man, and inflammatory peritoneal exudate neutrophils in mice. Second, inflammatory peritoneal exudate neutrophils and macrophages, elicited with the inflammatory agent proteose peptone, kill listeria just as well as do antigen-elicited peritoneal exudate neutrophils and macrophages, elicited presumably by T cell-dependent mechanisms 14. Resident cells are not bactericidal. In these experiments it didn't matter whether peritoneal exudate cells were collected from nonimmunized mice injected only with an inflammatory agent or from hyperimmunized mice resistant to 100-1000 LDso of Listeria that had been injected with Listeria antigens. When the
70
Departmentof Medidne, NationalJewish Center;and Departmentsof Pathologyand Medicine, Universityof ColoradoHealth SciencesCenter, Denver, CO80206, USA O 1986, ElsevierSciencePublishers B.V., Amsterdam 0167 4919/86/$02.00
Priscilla A. Campbell ability of these cells to kill Listeria was titrated, all cell populations killed equally. The hyperimmunized animals did differ, however, in the number of cells recruited to the peritoneal cavity in response to challenge with injected Listeria antigens: immunized mice recruited more neutrophils and macrophages than did nonimmunized mice. Miyata et a/.l~have also reported enhanced accumulation of peritoneal macrophages in immune mice challenged with Listeria antigens. This suggests that a critical event in developing resistance to these bacteria is the elicitation of an inflammatory response which results in recruitment of an increased number of cells which are capable of killing bacteria, rather than activation of phagocytes to higher levels of bactericidal activity. The third observation is that immune spleen T cells which transfer resistance to Listeria from immune mice to normal mice also transfer the ability to recruit inflammatory cells2°. Transfer of resistance and of an inflammatory response requires T cells and antigenic stimulation, and is dependent on the number of cells injected. Mice injected intraperitoneally with immune T cells recruited more macrophages and neutrophils to the peritoneal cavity after challenge with Listeria antigen than did mice injected with nonimmune T cells. But the phagocytes which were recruited in the presence of immune versus nonimmune T cells killed Listeria equally well. As before, macrophages and neutrophils which accumulated in the presence of immune T cells were no better at killing Listeria than phagocytes elicited in the presence of normal T cells; in the presence of immune T cells, more phagocytes were recruited. The fourth line of evidence implicating inflammatory cells in resistance to infection by facultative intracellular bacteria is derived from studies in genetically-resistant versus genetically-susceptible mice. The major defect in mice which are genetically-susceptible to listeriosis is in their ability to recruit cells to the peritoneal cavity when challenged with Listeria antigens or inflammatory agents 21 24 . C57BI/6 mice, which are resistant to Listeria, recruit more neutrophils at 4 h and macrophages at 48 h in response to Listeria challenge or challenge with an inflammatory agent than do A/J mice, which are susceptible to Listeria 21-23. Moreover, most strains of mice which are sensitive to Listeria are C5-deficient, while most strains of mice which are resistant to Listeria have normal
Immunology Today, voL Z No. 3, 1986
levels of C5 (Refs 21 and 22). When one attempts to reconstitute C5 levels in C5-deficient mice by injecting normal plasma, there is an increase in survival of the sensitive mice in response to Listeria and there is an increase in their ability to recruit inflammatory cells 22'23. These data again suggest that a defect in the ability of mice to recruit inflammatory cells effectively, perhaps because of a deficiency in complement-derived chemotactic factors, is primarily responsible for genetic susceptibility to Listeria. The fifth observation is that activation of macrophages to express tumoricidal activity does not necessarily result in expression of bactericidal activity. It was shown by Wing and Remington that macrophages from Trichinella- or Toxoplasmainfected mice differed in their abilities to kill tumor cells and intracetlular parasites depending on the time of in-vitro macrophage cultivation6'2~ Nacy et a/. were able to dissociate tumoricidal activity from the ability of macrophages to limit intracellular growth of Rickettsia by using different lymphokine fractions in vitro 7. Hopper and Cahil126 showed that macrophages with bactericidal activity were distinguished from those with tumoricidal activity by kinetics during secondary infection with Salmonella enteritidis, and by sedimentation velocity separation. We have shown that Bacille Calmette-Guerin (BCG) elicits peritoneal exudate macrophages which can kill tumor cells but which cannot kill Listeria or E. coil, although they are occasionally bacteriostatic for these organisms 27. On the other hand, peritoneal exudate macrophages elicited with proteose peptone are highly bactericidal but are unable to kill tumor cells. This has been demonstrated in both mice and hamsters, and using three different tumor targets 27. Thus it is possible to use selective stimuli to elicit populations of macrophages which express one activity but not the other. While there are many reports in the literature describing in-vivo and in-vitro stimuli which give rise to tumoricidal macrophages and there are several describing those stimuli which induce bactericidal capabilities, there are no reports as far as I am aware which demonstrate that a single population of cells can be induced to express both activities. Whether a single cell can express both tumoricidal and bactericidal capabilities, or not, remains to be shown. My colleagues and I find that peritoneal exudate macrophages from mice injected with BCG 2 weeks before harvest and with proteose peptone 2 days before harvest are both tumoricidal and bactericidal. But we have no evidence that the same cell is responsible for both activities, and suspect that it is not. Whether bactericidal and tumoricidal activities are dissociable because they are properties of macrophages at different stages of maturation, or because macrophages have been selectively induced to express a particular functional capacity by the stimuli they receive, or because of combinations of these and perhaps other unknown mechanisms, is not yet clear. The sixth line of evidence suggesting that the
rostrummacrophage activated to kill tumor cells may not be the cell exclusively responsible for killing facultative intracellular bacteria is derived from experiments using gamma interferon (IFN-~/)to stimulate macrophage function. Several laboratories have shown that IFN-~/, a T cell-derived lymphokine, can function as a macrophage activating factor which stimulates tumoricidal activity28-32. IFN-~/ has also been implicated as a lymphokine which stimulates macrophages to kill obligate intracellular parasites such as Leishmania, and Zoxoplasma 10'33. T-cell clones and hybrids which transfer resistance to listeriosis all secrete IFN-~ following antigenic challenge 34"3s. While there is evidence that recombinant IFN-T may participate in in-vivo induction of resistance against listeriosis36, evidence that it specifically triggers macrophages to express enhanced bactericidal activity is still lacking. In one recent report 37, monoclonal antibodies to IFN-~/ were reported to decrease the ability of a lymphokine preparation to slow growth of L. monocytogenes. But unfortunately the lymphokine preparation itself did not stimulate the macrophages to express either bactericidal or bacteriostatic activity. Rather in the presence of IFN-~/-containing supernatant, the bacterial population still quadrupled in 13 hours while in the absence of lymphokine it increased 18 times. IFN-~/ does not seem to activate macrophages to kill Listeria (P,A. Campbell, unpublished and S.H.E. Kaufmann, unpublished.). On the other hand, Douvas et a/. 38 showed that IFN-~/ stimulates human macrophages to become tumoricidal and leishmanicidal, but M. tuberculosis organisms grow better in these IFN-~-stimulated macrophages. Although a role for IFN-~/ in resistance against Listeria seems likely based on studies with Listeria-reactive T-cell clones, IFN-~/ does not seem to function by activating macrophages to express bactericidal activity. Its role in resistance to bacterial infection, if any, is yet to be clarified. My hypothesis is that early inflammatory phagocytes, cells recruited by antigen-specific T cells, are the primary mediators of resistance to infection by facultative intracellular bacteria. Whether T cells function by secreting lymphokines chemotactic for inflammatory cells, or perhaps by releasing agents which indirectly elicit inflammatory cells, is not yet known. The role of migration inhibition factor 39.40 • and IFN--y, T-cell products which have been implicated in resistance to listeriosis, is also not yet clear. Nevertheless, it seems that we should consider the hypothesis that T cells contribute significantly to resistance to infection by facultative intracellular bacteria, and perhaps by other organisms as well, by recruiting bactericidal inflammatory cells to the site of infection.
The authorthanks B. Canona,J. Cohen,J. Collins,J. Cook,A. Crowle, E. Goldson,P. Henson,K. Stedmanand W. Robertsfor critical review of the manuscript, and K. Crumrine and D. Thompson for secretarialassistance.
71
Immunology Today, vol. 7, No. 3, 1986
-rostrum References
1 Evans,R. and Alexander, P. (1972) Immunology 23, 615 2 Lohmann-Matthes, M.L, Ziegler, F.G and Fischer, H. (1973)
Eur. J. ImmunoL 3, 56 3 Piessens,W.F., Churchill, W.H. and David,J.R. (1975) J. ImmunoL 114, 293 4 Hibbs,J.B., Jr., Taintor, R.R.,Chapman, H.A., Jr. etaL (1977) Science 197, 279 5 Nogueira, N. and Cohn, Z.A. (1978)J. Exp. Med. 148, 288 6 Wing, E.J., KrahenbuhlJ.L. and Remington, J.S.(1979) Immunology 36,479 7 Nacy, C.A., Leonard, E.J.and Meltzer, MS. (1981) J. ImmunoL 126, 204 8 Walker, L. and Lowrie, D.B. (1981)Nature (London)293, 69 9 Murray, H.W., Byrne,G.I., Rothermel,C.D. etaL (1983) J. Exp, Med. 158, 234 10 Nathan, C.F., Murray, H.W., Wiebe, M.E. etaL (1983)J. Exp. Med. 158, 670 11 Steigbigel, R.T., Lambert, L.H., Jr. and Remington, J.S. (1974)J. Clin. Invest. 53,131 12 Peterson, P.K., Verhoef, J., Schmeling, D. etal. (1977) J. Infect. Dis. 136, 502 13 Czuprynski,CJ., Campbell, P.A. and Henson, P.M. (1983) J. ReticuloendotheL Soc. 34, 29 14 Czuprynski,C.J., Henson, P.M. and Campbell, P.A. (1984) J. Leukocyte Biol. 35, 193 15 Musson, R.A. (1983)Am. J. PathoL 111,331 16 Mackaness,G.B. (1962),/. Exp. Med. 116, 381 17 North R.J.(1970)J. Exp. Med. 132, 521 18 Mandel, T.E. and Cheers,C. (1980) Infect. Immun. 30, 851 19 Miyata, M., Mitsuyama, M., Ogata, N. etaL (1982) Immunology. 47, 247 20 Czuprynski,C.J., Henson, P.M. and Campbell, P.A. (1985) J. ImmunoL 134, 3449 21 Stevenson,M.M., Kongshavn, P.A. and Skamene, E. (1981)
J. Immunol. 127,402 22 Gervais,F., Stevenson,M and Skamene, E. (1984) J. Immunol. 132, 2078 23 Czuprynski, C.J., Canono, B.P., Henson, P.M. etaL (1985) Immunology. 55, 511 24 Kongshavn, P.A.L. Curr. Top. MicrobioL Immunol. (in press) 25 Wing, EJ., Gardner, I.D., Ryning, F.W. etal. (1977) Nature (London) 268, 642 26 Hopper, K.E. and Cahill, J.M (1983) J. ReticuloendotheL Soc. 33,443 27 Campbell, P.A., Czuprynski,C.J. and Cook, J.L (1984) J. Leukocyte Biol. 36, 293 28 Roberts,W.K. and Vasil,A. (1982)J. Interferon Res. 2, 519 29 Schultz, R.M and Kleinschmidt,WJ. (1983) Nature (London) 305,239 30 Pace,J.L., Russell,S.W., Schreiber, R.D. etaL (1983)Proc NatlAcad. Sci. USA 80, 3782 31 Pace,J.L, Russell,S.W., Torres, B.A. etaL (1983) J. ImmunoL 130, 2011 32 Spitalny, G.L. and Havell, E.A. (1984)J. Exp. Med. 159, 1560 33 Murray, H.W., Spitalny, G.L and Nathan, C.F. (1985) J. ImmunoL 134, 1619 34 Kaufmann, S.H.E.,Hahn, H., Berger, R. etal. (1983) Eur. J. ImmunoL 13,265 35 Kaufmann, S.H.E.(1985)in Monoclonal Antibodies Against Bacteria, Vol. I, pp. 233-267, Academic Press,New York 36 Kiderlen,A.F., Kaufmann, S.H.E.and Lohmann-Matthes, M.-L. (1984) Eur. J. Immunol. 14, 964 37 Schreiber, R.D., Hicks, LJ., Celada, A. etal. (1985) J. ImmunoL 134, 1609 38 Douvas,G.S., Looker, D.L., Vatter, A.E. etal. (1985) Infect. Immun. 50, 1 39 Kearns,R.J.and Campbell, P.A. (1983) Int. Arch. Allergy AppL Immunol. 70, 59 48 Sperling, U., Kaufmann, S.H.E.and Hahn, H. (1984)Infect. Immun. 46, 111
T-cell ontogeny: the role of a stimulator suppressor cell The thymus presents two major problems in cellular differentiation. How is self-non-self discrimination achieved in developing thymocytes? What determines the development of T-cell classes? In this discussion, Alan Herbert and James Watson propose a mechanism for regulating T-cell differentiation which involves the alternative pathway of T-cell activation. They postulate that T cells with a stimulator-suppressor phenotype stimulate resting helper T cells (Th) to produce interleukin 2 (IL-2) and suppress T cells which have bound antigen through antigenspedfic receptors by preventing induction of IL-2 receptors. Stimulator-suppressor T cells therefore suppress the donal expansion of T cells in an antigen-specific manner, yet promote their own clonal expansion in a manner independent of antigen. They further suggest that the molecule responsible for suppression is the product of the "1 genes known to rearrange in T cells. Human T cells bear three classes of cell surface receptors involved in activation: classical antigenbinding receptors which are distributed clonally on
72
Department of lmmunobiology, Universityof Auckland, PrivateBag Auckland, New Zealand (~) 1986, Elsevier Science Publishers B.V., Amsterdam
0167 -4919/86/$02.00
Alan G. Herbertand JamesD. Watson T ceils; a sheep erythrocyte-binding receptor present on all T cells; and the IL-2 receptor. Equivalents of these three types of receptor probably exist in T ceils of all mammalian species. In this article we will discuss mouse T lymphocytes and their development and will use the term 'E receptor' to describe the murine equivalent of the non-clonally specific structure which on human T cells binds sheep erythrocytes. T-cell activation usually occurs as a consequence of antigen-binding and leads to the expression of iL-2 receptors. Genes which encode antigen binding receptors have been identified in T cells by screening cDNA libraries for genes that are no longer in a germ line configuration. In each T cell, there are at least three genes which can undergo rearrangement, all of which have hydrophobic leader sequences 1 5 The ~ and 13 gene products combine to form ~13 heterodimers that participate in the MHC-restricted activation of T cells by antigen 6-8. The ~/ gene has limited diversity in its