Immunology Today, vol. 5, No. 7, 1984
ffl
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) Do natural killer cells regulate B-cell activity? K. James and A. W. S. Ritchie* For the past tenyears or so the natural killer (NK) cell has masqueraded as the cell par excellence in immunosurveillance1. In this article Keith James and Alistair Ritchie discuss the evidence (both direct and indirec0 for ArK cells' influence on the differentiation, proliferation and activity of B cells.
The" N K cell first gained pre-eminence because it helped explain a number of observations which had troubled tumour immunologists. These included the lack of specificity of many in-vitro studies on the cell-mediated destruction of tumour cell targets and the disconcerting observation that athymic mice had no greater incidence of primary spontaneous tumours than their normal counterparts 2'3. Continuing interest in the possible immunosurveiUance role of these cells has been sustained in recent years 2 by observations that their activity can be modulated by interferon and interleukin 2 (see, for example, Ref. 4) and that N K cells themselves may synthesize interferon 5. While there is still argument with respect to the importance of NK cells in surveillance 6, evidence is beginning to emerge that suggests that these cells may have a more .fundamental physiological role, namely in the regulation ofhaematopoiesis and lymphopoiesis. The most convincing evidence for NK cells' influence on the differentiation, proliferation and activity of B cells is the demonstration that activated mouse NK cells lyse lipopolysaccharide-activated lymphocytes in a nonMHC-restricted manner and suppress the primary plaque-forming cell response to sheep erythrocytes, chicken erythrocytes and trinitrophenylated 'Ficoll'7.°. Mouse N K cells also suppress ongoing IgM responses in vivo or when added to cultures immunized in vitro 2 or 3 days previously 9. H u m a n blood N K cells readily suppress pokeweed mitogen-driven B-cell differentiation'° and can be activated by mitomycin-treated 'normal' human B-cell lines n. Furthermore, such activated cells appear capable of lysing the B-cell line used for activation as well as conventional NK cell targets. Some of the inhibitory effects observed can be achieved with extremely small numbers of N K cells: for instance, cloned mouse N K cells induced suppression when they comprised only 0.2 % of the total cells in the culture 8. On a cell-for-cell basis human N K cells appear to be more inhibitory than suppressor T cells 1°. However, suboptimal ratios of N K to non-NK cells enhance B-cell responses 9. There is also evidence from immunocytochemical studies that cells which stain with N K cell-specific monodonal HNK-1 or Leu-7 are preferentially localized in the B-cell areas of lymphoid tissue12-1L This close juxtaposition of N K cells and B cells in lymphoid tissue, together Department of Surgery, University of Edinburgh, Edinburgh EH8 9AG, UK. *Department of Urology, Royal Liverpool Hospital, Liverpool L7 8XP, UK.
with the cytolytic and inhibitory effects discussed above, lends support to the view that N K cells may play some regulatory role in vivo. If this is indeed true, one might expect to fmd enhanced B-cell proliferation and other manifestations of increased B-cell activity in patients or animals whose NK-cell systems are impaired. This is so in patients with the acquired immune deficiency syndrome 15. The high incidence of progressive lymphoproliferative disorders seen in patients with the Chekdiak-Higashi syndrome" and the elevated IgM levels in aged patients 0might be due to impaired N K cell-dependent homeostatic mechanisms. Whether or riot similar perturbations in B-cell control occur in other groups of patients with abnormal N K cell function remained to be confirmed. The means whereby N K cells (activated or otherwise) recognize and subsequently kill B cells or modify their functions has still to be established. Their influence might be direct or indirect, or both. Direct mechanisms would depend upon NK cells' being able to recognize B cells and a number of suggestions have been made about how they might do so. They may, for example, interact with the transferrin receptors on B cells 16- a particu!arly important observation because the expression of transferrin receptors on lymphocyte surfaces is greatly enhanced before and during cell proliferation 17. We have proposed n that NK cells might also interact with IgD molecules on B-cell surfaces and that this interaction may influence the maturation of antibody affinity, a hypothesis which has still to be tested. It is apparent, however, that the lysis of B cells by N K cells is not MHC-restricted 8. If NK cells' influence on B-cell activity is indirect, two possible mechanisms have been proposed 9,t°. One postulate is that unactivated N K cells interfere with T helper activity 1°. This is an attractive suggestion but it should be noted that in an activated state NK cells have no effect on helper T-cell activity 0. An alternative suggestion is that NK cells induced after immunization may regulate both the primary and anamnestic response by interacting with a target that is expressed upon accessory cells after their association with antigenL This interaction, it has been argued, could modify B-cell activity by impairing antigen presentation or the production and release of interleukin 1 and other soluble factors governing the proliferation and secretion of antibody-forming cells 9. The hypothesis that NK ceils may regulate B-cell activity is an appealing one but several questions remain unanswered. Why, for example, are there such marked differences in the number and cytolytic ability of NK cells from different lymphoid tissues? Are impairments in NK© I ~ 4 , Elsevier Science l~bllahers B.V., Anmterdam
0167 -- 4919/84/~)2.00
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Immunology Today, vol. 5, No. 7, 1984
cell function always accompanied by defective B-cell control? If NK cells impair B-cell function via transferrin receptors, do they interact with and influence all rapidly proliferating cells, malignant or otherwise? They seem to have an effect on antigen-presenting cells 9, helper T cells, and the development of haemapoietic tissue18 Nevertheless a certain amount of selectivity for B cells could occur if additional structures were involved in recognition 16, as has been proposed for interaction with accessory cells 9. This could involve, for example, both a transferrin receptor and an Fc receptor. Furthermore, such a mechanism might permit the elimination of clones producing antibodies of a particular isotype or specificity. Alternatively it could be argued that B cells might be more susceptible to this kind of control simply because of the nearness of N K cells in B areas or because they are less able to repair themselves after NK cell-inflicted injury 16. Although many more studies will be necessary before we can claim that NK cells are yet another component of the complex immunoregulatory networks, this hypothesis is worthy of further consideration. As others have emphasized, the primary role of N K cells in vivo may be the regulation of normal cells 16'19, cancer surveillance being the indirect and inevitable benefit of a system which can react rapidly against unwanted differentiation or foreign invaders 2. Note added in proof: Since this paper was submitted additional evidence has emerged to show that N K cells regulate antibody pro-
duction by human lymphoblastoid cell lines. (Breva, J. A., Targan, S. and Stevens, R. H. (1984)J. Immunol. 132,611). []
References 1 Herberman, R. B. (1982) ArK Cells and OtherNatural Effeetor Cells, Academic Press, New York 2 Stutman, O. (1981) lramunol. Today 2, 205-208 3 Bloom, B. R. (1982) Nature(London) 300, 213-215 4 Kuriboyashi, K., Gillis, S., Kern, D. E. and Henney, C. S. (1981) , f Immunol. 126, 2321-2327 5 Timonon, T., Saksela, E., Virtanean, I. and Cantell, K. (1980) Eur. J. Immunol. I0, 422-427 6 Stutman, O.(1983)Proceedingsofthe5thlnternationalCongresso.flmmunology, Kyoto, Japan 7 Nabel, G., Buealo, L. R., Allard, J. et aL (1981)J. Exp. Med. 153, 1582-1591 8 Nabel, G., Allard, W. J. and Cantor, H. (1982)J. Exp. Med. 156, 658-663 9 Abruzzo, L. V. and Rowley, D. A. (1983) Science222, 581-583 10 Arai, S., Yamamoto, H., Itah, K. and Kumagai, K. (1983)J. ImmunoL 131,651-657 11 Targan, S. R. and Oseas, R. (1983)J. Imrnanol. 130, 2671-2674 12 Ritehie, A. W. S., James, K. and Micklem, H. S. (1983) Clin. Exp, Immunol. 51,439-447 13 Si, L. and Whiteside, T. L. (1983)J. Immunol. i30, 2149-2155 t4 Banerjee, D. and Thibert, R. F. (1983) Nature(London) 304, 270-272 15 Talal, N. (1983) Immunol. Today 4, 180-183 16 Vodinelich, L., Sutherland, R., Schneider, C. et al. (1983) Proc. Natl Acad. Sci. USA 80, 835-839 17 Brock, J. H. and Mainou-Fowler, T. (1983) Immunol. Today 4, 347-351 18 Kiessling, R. (1983) Proceedings of the 5th International Congress of Immunology, Kyoto, Japan 19 Langman, R. (1980) Nature (London) 286, 208
The origin and significance of class discrimination in immunity R. E.
Langrnan
In this purely speculative article, Rod Langman develops the theme that a decision-making process requires information which distinguishes the choices and an interpretive mechanism which links a choice with an appropriate consequence. An immune response takes place after two antigendependent discriminatory decisions are made by the immune system. Prior to immunization there is the self-non-self discrimination, then, after immunization, there are two levels of class discrimination; the first of which results in either cell-mediated (CMI) or humoral (Ig) immunity and, within the humoral class, at a second level only one or a few immunoglobulin H-chain isotypes (for example IgM, IgG, etc.) are produced. In order for the immune system to make a decision, information is required that allows a choice between the alternatives. Thus, for the self-non-self discrimination antigen is required for the induction of both responsiveness to nonself and unresponsiveness to self. The immune system then informs itself whether antigen is persistent (i.e. self) or transient (i.e. non-self).
Developmental Biology Laboratory, Salk Institute Biological Studies, LaJolla, CA 92138-9216, USA. © 1984,
Elsevier Science
PublishersB.V.,Amsterdam 0167- 4919/84/$02.170
for
To choose between C M I and humoral responses (including Ig H-chain isotype), the immune system requires additional information. Since all effector functions are directed at antigen via an antigen-specific recognition system, in an unregulated system this results in competition between different classes of effector function for the antigen. If different effector functions reflect the different requirements for antigen elimination, it would make biological sense if the immune system could regulate the class of response according to the effectiveness (or ineffectiveness) of a particular effector function in antigen elimination. Assuming that the immune system was selected evolutionarily as a mechanism for eliminating pathogens, it follows that pathogenic micro-organisms and viruses under the strong selective pressure of an immune response will tend to rapidly escape selection. Thus, by constantly monitoring the effectiveness of a given class of response in eliminating antigen, varying forms of a pathogen can be tracked with necessary changes in the class of response.
ffl
193
) Do natural killer cells regulate B-cell activity? K. James and A. W. S. Ritchie* For the past tenyears or so the natural killer (NK) cell has masqueraded as the cell par excellence in immunosurveillance1. In this article Keith James and Alistair Ritchie discuss the evidence (both direct and indirec0 for ArK cells' influence on the differentiation, proliferation and activity of B cells.
The" N K cell first gained pre-eminence because it helped explain a number of observations which had troubled tumour immunologists. These included the lack of specificity of many in-vitro studies on the cell-mediated destruction of tumour cell targets and the disconcerting observation that athymic mice had no greater incidence of primary spontaneous tumours than their normal counterparts 2'3. Continuing interest in the possible immunosurveiUance role of these cells has been sustained in recent years 2 by observations that their activity can be modulated by interferon and interleukin 2 (see, for example, Ref. 4) and that N K cells themselves may synthesize interferon 5. While there is still argument with respect to the importance of NK cells in surveillance 6, evidence is beginning to emerge that suggests that these cells may have a more .fundamental physiological role, namely in the regulation ofhaematopoiesis and lymphopoiesis. The most convincing evidence for NK cells' influence on the differentiation, proliferation and activity of B cells is the demonstration that activated mouse NK cells lyse lipopolysaccharide-activated lymphocytes in a nonMHC-restricted manner and suppress the primary plaque-forming cell response to sheep erythrocytes, chicken erythrocytes and trinitrophenylated 'Ficoll'7.°. Mouse N K cells also suppress ongoing IgM responses in vivo or when added to cultures immunized in vitro 2 or 3 days previously 9. H u m a n blood N K cells readily suppress pokeweed mitogen-driven B-cell differentiation'° and can be activated by mitomycin-treated 'normal' human B-cell lines n. Furthermore, such activated cells appear capable of lysing the B-cell line used for activation as well as conventional NK cell targets. Some of the inhibitory effects observed can be achieved with extremely small numbers of N K cells: for instance, cloned mouse N K cells induced suppression when they comprised only 0.2 % of the total cells in the culture 8. On a cell-for-cell basis human N K cells appear to be more inhibitory than suppressor T cells 1°. However, suboptimal ratios of N K to non-NK cells enhance B-cell responses 9. There is also evidence from immunocytochemical studies that cells which stain with N K cell-specific monodonal HNK-1 or Leu-7 are preferentially localized in the B-cell areas of lymphoid tissue12-1L This close juxtaposition of N K cells and B cells in lymphoid tissue, together Department of Surgery, University of Edinburgh, Edinburgh EH8 9AG, UK. *Department of Urology, Royal Liverpool Hospital, Liverpool L7 8XP, UK.
with the cytolytic and inhibitory effects discussed above, lends support to the view that N K cells may play some regulatory role in vivo. If this is indeed true, one might expect to fmd enhanced B-cell proliferation and other manifestations of increased B-cell activity in patients or animals whose NK-cell systems are impaired. This is so in patients with the acquired immune deficiency syndrome 15. The high incidence of progressive lymphoproliferative disorders seen in patients with the Chekdiak-Higashi syndrome" and the elevated IgM levels in aged patients 0might be due to impaired N K cell-dependent homeostatic mechanisms. Whether or riot similar perturbations in B-cell control occur in other groups of patients with abnormal N K cell function remained to be confirmed. The means whereby N K cells (activated or otherwise) recognize and subsequently kill B cells or modify their functions has still to be established. Their influence might be direct or indirect, or both. Direct mechanisms would depend upon NK cells' being able to recognize B cells and a number of suggestions have been made about how they might do so. They may, for example, interact with the transferrin receptors on B cells 16- a particu!arly important observation because the expression of transferrin receptors on lymphocyte surfaces is greatly enhanced before and during cell proliferation 17. We have proposed n that NK cells might also interact with IgD molecules on B-cell surfaces and that this interaction may influence the maturation of antibody affinity, a hypothesis which has still to be tested. It is apparent, however, that the lysis of B cells by N K cells is not MHC-restricted 8. If NK cells' influence on B-cell activity is indirect, two possible mechanisms have been proposed 9,t°. One postulate is that unactivated N K cells interfere with T helper activity 1°. This is an attractive suggestion but it should be noted that in an activated state NK cells have no effect on helper T-cell activity 0. An alternative suggestion is that NK cells induced after immunization may regulate both the primary and anamnestic response by interacting with a target that is expressed upon accessory cells after their association with antigenL This interaction, it has been argued, could modify B-cell activity by impairing antigen presentation or the production and release of interleukin 1 and other soluble factors governing the proliferation and secretion of antibody-forming cells 9. The hypothesis that NK ceils may regulate B-cell activity is an appealing one but several questions remain unanswered. Why, for example, are there such marked differences in the number and cytolytic ability of NK cells from different lymphoid tissues? Are impairments in NK© I ~ 4 , Elsevier Science l~bllahers B.V., Anmterdam
0167 -- 4919/84/~)2.00
194
Immunology Today, vol. 5, No. 7, 1984
cell function always accompanied by defective B-cell control? If NK cells impair B-cell function via transferrin receptors, do they interact with and influence all rapidly proliferating cells, malignant or otherwise? They seem to have an effect on antigen-presenting cells 9, helper T cells, and the development of haemapoietic tissue18 Nevertheless a certain amount of selectivity for B cells could occur if additional structures were involved in recognition 16, as has been proposed for interaction with accessory cells 9. This could involve, for example, both a transferrin receptor and an Fc receptor. Furthermore, such a mechanism might permit the elimination of clones producing antibodies of a particular isotype or specificity. Alternatively it could be argued that B cells might be more susceptible to this kind of control simply because of the nearness of N K cells in B areas or because they are less able to repair themselves after NK cell-inflicted injury 16. Although many more studies will be necessary before we can claim that NK cells are yet another component of the complex immunoregulatory networks, this hypothesis is worthy of further consideration. As others have emphasized, the primary role of N K cells in vivo may be the regulation of normal cells 16'19, cancer surveillance being the indirect and inevitable benefit of a system which can react rapidly against unwanted differentiation or foreign invaders 2. Note added in proof: Since this paper was submitted additional evidence has emerged to show that N K cells regulate antibody pro-
duction by human lymphoblastoid cell lines. (Breva, J. A., Targan, S. and Stevens, R. H. (1984)J. Immunol. 132,611). []
References 1 Herberman, R. B. (1982) ArK Cells and OtherNatural Effeetor Cells, Academic Press, New York 2 Stutman, O. (1981) lramunol. Today 2, 205-208 3 Bloom, B. R. (1982) Nature(London) 300, 213-215 4 Kuriboyashi, K., Gillis, S., Kern, D. E. and Henney, C. S. (1981) , f Immunol. 126, 2321-2327 5 Timonon, T., Saksela, E., Virtanean, I. and Cantell, K. (1980) Eur. J. Immunol. I0, 422-427 6 Stutman, O.(1983)Proceedingsofthe5thlnternationalCongresso.flmmunology, Kyoto, Japan 7 Nabel, G., Buealo, L. R., Allard, J. et aL (1981)J. Exp. Med. 153, 1582-1591 8 Nabel, G., Allard, W. J. and Cantor, H. (1982)J. Exp. Med. 156, 658-663 9 Abruzzo, L. V. and Rowley, D. A. (1983) Science222, 581-583 10 Arai, S., Yamamoto, H., Itah, K. and Kumagai, K. (1983)J. ImmunoL 131,651-657 11 Targan, S. R. and Oseas, R. (1983)J. Imrnanol. 130, 2671-2674 12 Ritehie, A. W. S., James, K. and Micklem, H. S. (1983) Clin. Exp, Immunol. 51,439-447 13 Si, L. and Whiteside, T. L. (1983)J. Immunol. i30, 2149-2155 t4 Banerjee, D. and Thibert, R. F. (1983) Nature(London) 304, 270-272 15 Talal, N. (1983) Immunol. Today 4, 180-183 16 Vodinelich, L., Sutherland, R., Schneider, C. et al. (1983) Proc. Natl Acad. Sci. USA 80, 835-839 17 Brock, J. H. and Mainou-Fowler, T. (1983) Immunol. Today 4, 347-351 18 Kiessling, R. (1983) Proceedings of the 5th International Congress of Immunology, Kyoto, Japan 19 Langman, R. (1980) Nature (London) 286, 208
The origin and significance of class discrimination in immunity R. E.
Langrnan
In this purely speculative article, Rod Langman develops the theme that a decision-making process requires information which distinguishes the choices and an interpretive mechanism which links a choice with an appropriate consequence. An immune response takes place after two antigendependent discriminatory decisions are made by the immune system. Prior to immunization there is the self-non-self discrimination, then, after immunization, there are two levels of class discrimination; the first of which results in either cell-mediated (CMI) or humoral (Ig) immunity and, within the humoral class, at a second level only one or a few immunoglobulin H-chain isotypes (for example IgM, IgG, etc.) are produced. In order for the immune system to make a decision, information is required that allows a choice between the alternatives. Thus, for the self-non-self discrimination antigen is required for the induction of both responsiveness to nonself and unresponsiveness to self. The immune system then informs itself whether antigen is persistent (i.e. self) or transient (i.e. non-self).
Developmental Biology Laboratory, Salk Institute Biological Studies, LaJolla, CA 92138-9216, USA. © 1984,
Elsevier Science
PublishersB.V.,Amsterdam 0167- 4919/84/$02.170
for
To choose between C M I and humoral responses (including Ig H-chain isotype), the immune system requires additional information. Since all effector functions are directed at antigen via an antigen-specific recognition system, in an unregulated system this results in competition between different classes of effector function for the antigen. If different effector functions reflect the different requirements for antigen elimination, it would make biological sense if the immune system could regulate the class of response according to the effectiveness (or ineffectiveness) of a particular effector function in antigen elimination. Assuming that the immune system was selected evolutionarily as a mechanism for eliminating pathogens, it follows that pathogenic micro-organisms and viruses under the strong selective pressure of an immune response will tend to rapidly escape selection. Thus, by constantly monitoring the effectiveness of a given class of response in eliminating antigen, varying forms of a pathogen can be tracked with necessary changes in the class of response.
