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T-cell regulation of human B-cell activation. A reappraisal of the role of interleukin 2
Immunology Today, voL 6, No. 9, 1985
258
-
)
T-cell regulation of human B-cell activation. A reappraisal of the role of interleukin 2. Frank Miedema and CornelisJ. M. Melief The polyclonal activator pokeweed mitogen ( P W M ) has been widely used to study regulatory mechanisms in the differentiation of human B cells into immunoglobulin (Ig) secreting plasma cells (for review see Ref. 1). P W M induced proliferation and differentiation of human B cells is strictly T-cell dependent and may provide a means to study the immunoregulatory activities of T-cell subsets 1 3. Furthermore, several antigen-non-specific T-cell derivedfactors have been shown to regulate B-cell activation 4'5. One class of solublefactors, designated B-cell growth factors (BCGF), supports growth of human B cells, when pre-activated by anti-Ig antibody or Staphylococcus aureus Cowan strain I (SA C) 4,5. A second class offactors, B-cell differentiation factors (BCD F) induces terminal differentiation of activated B cells into Ig secretingplasma cellJ. Here Frank Miedema and Cornelius Meliefexamine the claims and counterclaims concerning the influence of interleukin 2, a T-cell growth factor, on B cells and conclude that interleukin 2 has a pivotal role in the humoral immune response. The role of Interleukin-2 (IL-2) in B-cell activation is still controversial. Although a direct effect of IL-2 on resting murine B cells has been suggested by some investigators 6"7, others claim that IL-2 did not act on resting murine B cells 8-1°. In our laboratory, no direct effect of IL-2 on T-cell depleted peripheral blood leukocytes 11 or on purified resting h u m a n B cells~2 could be demonstrated. However, the finding that IL-2 was capable of inducing Ig synthesis in peripheral blood mononuclear cells suggested an indirect effect of IL-2 on B-cell activation TM. This Ig inducing capacity was shown to be mediated by IL-2 itsell~2 and was dependent on the presence o f T 4 +8 helper cells ~ . This direct effect of IL-2 on unstimulated peripheral blood T cells is in agreement with the finding that IL-2 induces a proliferative response in unstimulated T cells (Roosnek, Brouwer and Aarden, unpublished observations). The finding that anti-Tac, a monoclonal antibody directed against the h u m a n IL-2 receptor, abrogated both P W M - and IL-2driven Ig synthesis "-~4 and that P W M induces IL-2 production" indicates that IL-2 plays an important role in T-cell dependent B-cell activation. O u r results are in agreement with observations reported by Teranishi et al. 15 who showed that IL-2 induces Ig synthesis in SACstimulated B cells only in the presence of T-helper cells. Moreover, it has been shown that, in the mouse, IL-2 did not act directly on B cells but it induced T cells to release B C D F (Ref. 9) and B C G F (Ref. 10). Hence, T-helper activity on P W M - d r i v e n Ig synthesis appears to be at least a two-step process: 1. induction of IL-2 production; 2. IL-2-induced release from T4 ÷ cells of helper factors for B-cell activation. In this model IL-2 production is a prerequisite for T-helper activity in the P W M - d r i v e n system. T4 ÷ cells from the blood of healthy donors always produce IL-2 and deliver helper signals to B cells, thus allowing no clear-cut separation of these functional Central Laboratory of the Netherlands Red Gross Blood Transfusion Service, incorporating the Department of Experimental and Clinical Immunology of the University of Amsterdam, Amsterdam, The Netherlands. © 1985, Elsevier Science Publishers B . V , Amsterdam
0167 - 4919185/$02.00
antigen/PWM
interleukin-2
@ CTL
l\ ~
""BCGFf @
T memorycells
Ig plasecreting smacells
Fig. 1. Central role for Interleukin-2 in both the humoral and the cellular immune response. / • Antigen-MHC complex • Interleukin-2receptors / ,.? T-cell receptor / y Immunoglobulin ) A BCGF receptors [] BCDF receptors
Immunology Today, voL 6, No. 9, 1985
activities. To test this model further we took advantage of the availability of'clonal' neoplastic T4 ÷ cells of patients with a mature T-cell malignancy. Four out of 20 neoplastic T4 + cell populations devoid of helper activity in the P W M system, which failed to produce IL-2 upon P W M stimulation, provided excellent helper activity in the presence of exogenous IL-2 (Miedema et aL, unpublished observations). These data are compatible with the hypothesis that IL-2 production is required for the induction of T4 + cell-derived helper signals for B-cell differentiation. A synergistic effect of IL-2 and other T-cell factors on activatedB cells, however, seems likely since very recently from different laboratories strong evidence was reported that activated B cells express IL-2 receptors ~6-19. Indeed, activated B and T cells express very similar, if not identical, receptors for IL-2 ~7-19. With regard to the functional significance of the expression of IL-2 receptors on B cells, it is now clear that activated, IL-2 receptor-bearing B cells proliferate in response to human recombinant IL2 ~9. The proliferating cells were T3- (< 2 %), Tac + and surface Ig + (> 90%) and thus indeed were B cells 19. Similar data were obtained by others ~5,~s.The question of whether IL-2, apart from BCGF activity, also has B C D F activity has not yet been settled. Preliminary results suggest that this is not the case 18 or that IL-2 has only a marginal BCDF effect on B cells ~5'2°. In summary, the following model for the regulation of human B-cell differentiation and proliferation by T cells can be postulated (Fig. 1): P W M or antigen induce IL-2 production and a rapid enhancement of IL-2 receptor expression on resting T cells. The expression of IL-2 receptors is further regulated by IL-2. This has been demonstrated with peripheral blood T cells 2~'22and with antigen-specific human T-ceU clones 23. This causes, possibly in an autocrine fashion, T-cell proliferation 23 and the IL-2-induced release of helper factors for B-cell growth and differentiation 9 ,2.25. In addition to the induction of T-cell proliferation, IL-2, like BCGF, supports the growth of B cells, once activated 15'18'~9, and induces B C D F release by TR cells. Possibly, BCDF-like molecules can also be induced by an IL-2-independent route, as demonstrated with T cells from a c o m m o n variable immuno-deficiency patient 24. The suppressive effect of T8 + cells on PWM-induced B-cell differentiation occurs not at the level of IL-2 synthesis t~ but most likely at the level of B C G F / B C D F production by helper cells 25. Taken together, the data available at present fit into a model with a pivotal role for IL-2, not only in the regulation of the cellular immune response, but also in the regulation of the humoral immune response.
259
Acknowledgement The authors thank Drs L. A. Aarden and R. W. Sauerwein for stimulating discussions and valuable suggestions. Our work was supported by the Koningin Wilhelmina Fonds/Netherlands Cancer Organization, grant CLB-80~2. Editor's note Since this article was submitted for publication, three recent papers have supported the hypothesis it contains; Nagakawa, T. et al. (1985)J. ImmunoL 134, 3959 Boyd, A. elal. (1985)J. Immunol. 134, 2387 [=~ Lentz, O. etal. (1985)J. Exp. Med. 161, 1225
References 1 2 3 4 5
6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
Waldmann, T. A. and Broder, S. (1982)Adv. Immunol. 32, 1-63 Thomas, Y., Rogozinski, L. and Chess, L. (1983) Immunol. Rev. 74, 113-128 Reinherz, E. L., Meuer, S. C. and Schlossman, S. F. (1983) Immunol. Rev. 74, 83-112 Muraguchi, A. and Fauei, A. S. (1982)J. ImmunoL 129, 1104-1108 Kishimoto, T., Yoshizaki, K. Kimoto, M., Okada, M., Kuritani, T., Kikutani, H., Shimizu, K., Nakagawa, T., Nakagawa, N., Miki, Y., Kishi, H., Fukunaga, K., Yoshikito, T. and Taga, T. (1984)Immunol. Reo. 78, 97 118 Leibson, H.J., Marraek, P. and Kappler, J. (1982)dt. ImmunoL 129, 1398-1402 Parker, D. C. (1982)J. Immunol. 129,469-474 Pure, E , Isackson, P. C., Paetkan, V., Caplan, B., Vitetta, E. S. and Krammer, P. H. (1982)J. ImrnunoL 129, 2420-2425 Inaba, K., Granelli-Piperno, A. and Steinman, R. M. (1983)J. Exp. Med. 158, 2040-2057 Howard, M., Matis, L., Malek, T. R., Seherach, E., Kell, W. Cohen, D., Nakaniski, K. and Paul, W. E. (1983),]. Exp. Med. 158, 2024-2039 Miedema, F., van Oostveen,J. W., Sauerwein, R. W., Terpstra, F. G., Aarden, L.A. and Melief, C.J.M. (1985)Eur.J. ImmunoL 15,107-112 Sauerwein, R. W., van der Meer, W. G.J., Dra~er, A. and Aarden, L. A. Eur. J. ImmunoL in press Leonard, W. J., Depper, J. M., Uchiyama, T., Smith, K. A., Waldmann, T. A. and Greene, W. C. (1982) Nature (London) 300, 267-269 Depper, J. M., Leonard, W.J., Robb, R. J., Waldmann, T. A. and Greene, W. C. (1983),]. Immunol. 131,690-697 Teranishi, T., Hirano, T., Lin, B-H. and Onoue, K. (1984)J. Immunol. 133, 3062-3067 Tsudo, M., Uchiyama, T. and Uchino, H. (1984)J. Exp. Med. 160, 612-617 Waldmann, T. A., Goldman, C. K., Robb, R. J., Depper, J. M., Leonard, W. J., Sharrow, S. O., Bongiovanni, K. F., Korsmeyer, S.J. and Greene, W. C. (1984)J. Exp. Med. 160, 1450-1466 Jung, L. R. L., Hara, T. and Fu, S. M. (1984)J. Exp. Med. 160, 1597-1602 Mingari, M. C., Gerosa, F., Carra, G., Accolla, R. S., Moretta, A., Zubler, R. H., Waldmann, T. A. and Moretta, L. (1984) Nature (London) 312,641-642 Ralph, P., Yeong, G., Welte, K., Mertelsmann, R., Rabin, H., Henderson, L. E., Souza, L. M., Boone, T. C. and Robb, R.J. (1984) ,]. Immunol. 133, 2442-2445 Welte, K., Andreff, M., Platzner, E., Holloway, K., Rubin, B. Y., Moore, M. A. S. and Mertelsman, R. (1984)J. Exp. Med. 160, 1391-1403 Rheem, G. H. and Yeh, N-S. (1984) Science 225,429-430 Meuer, S. C , Hnssey, R. E., Cantrell, D. A., Hodgdon, J. C., Schlossman, S. F., Smith, K. A. and Reinherz, E. L. (1984)Proc. Natl Acad. Sci. USA 81, 1509-1513 Saiki, O., Shimiz,a, M., Saeki, Y., Kishimoto, S. and Kishimoto, T. (1984)J. ImmunoL 133, 1920-1924 Thomas, Y., Sosman,J., Rogozinski, L., Trigoyen, O., Kung, P. C., Gotdstein, G. and Chess, L. (1981)J. ImmunoL 126, 1948 1951
258
-
)
T-cell regulation of human B-cell activation. A reappraisal of the role of interleukin 2. Frank Miedema and CornelisJ. M. Melief The polyclonal activator pokeweed mitogen ( P W M ) has been widely used to study regulatory mechanisms in the differentiation of human B cells into immunoglobulin (Ig) secreting plasma cells (for review see Ref. 1). P W M induced proliferation and differentiation of human B cells is strictly T-cell dependent and may provide a means to study the immunoregulatory activities of T-cell subsets 1 3. Furthermore, several antigen-non-specific T-cell derivedfactors have been shown to regulate B-cell activation 4'5. One class of solublefactors, designated B-cell growth factors (BCGF), supports growth of human B cells, when pre-activated by anti-Ig antibody or Staphylococcus aureus Cowan strain I (SA C) 4,5. A second class offactors, B-cell differentiation factors (BCD F) induces terminal differentiation of activated B cells into Ig secretingplasma cellJ. Here Frank Miedema and Cornelius Meliefexamine the claims and counterclaims concerning the influence of interleukin 2, a T-cell growth factor, on B cells and conclude that interleukin 2 has a pivotal role in the humoral immune response. The role of Interleukin-2 (IL-2) in B-cell activation is still controversial. Although a direct effect of IL-2 on resting murine B cells has been suggested by some investigators 6"7, others claim that IL-2 did not act on resting murine B cells 8-1°. In our laboratory, no direct effect of IL-2 on T-cell depleted peripheral blood leukocytes 11 or on purified resting h u m a n B cells~2 could be demonstrated. However, the finding that IL-2 was capable of inducing Ig synthesis in peripheral blood mononuclear cells suggested an indirect effect of IL-2 on B-cell activation TM. This Ig inducing capacity was shown to be mediated by IL-2 itsell~2 and was dependent on the presence o f T 4 +8 helper cells ~ . This direct effect of IL-2 on unstimulated peripheral blood T cells is in agreement with the finding that IL-2 induces a proliferative response in unstimulated T cells (Roosnek, Brouwer and Aarden, unpublished observations). The finding that anti-Tac, a monoclonal antibody directed against the h u m a n IL-2 receptor, abrogated both P W M - and IL-2driven Ig synthesis "-~4 and that P W M induces IL-2 production" indicates that IL-2 plays an important role in T-cell dependent B-cell activation. O u r results are in agreement with observations reported by Teranishi et al. 15 who showed that IL-2 induces Ig synthesis in SACstimulated B cells only in the presence of T-helper cells. Moreover, it has been shown that, in the mouse, IL-2 did not act directly on B cells but it induced T cells to release B C D F (Ref. 9) and B C G F (Ref. 10). Hence, T-helper activity on P W M - d r i v e n Ig synthesis appears to be at least a two-step process: 1. induction of IL-2 production; 2. IL-2-induced release from T4 ÷ cells of helper factors for B-cell activation. In this model IL-2 production is a prerequisite for T-helper activity in the P W M - d r i v e n system. T4 ÷ cells from the blood of healthy donors always produce IL-2 and deliver helper signals to B cells, thus allowing no clear-cut separation of these functional Central Laboratory of the Netherlands Red Gross Blood Transfusion Service, incorporating the Department of Experimental and Clinical Immunology of the University of Amsterdam, Amsterdam, The Netherlands. © 1985, Elsevier Science Publishers B . V , Amsterdam
0167 - 4919185/$02.00
antigen/PWM
interleukin-2
@ CTL
l\ ~
""BCGFf @
T memorycells
Ig plasecreting smacells
Fig. 1. Central role for Interleukin-2 in both the humoral and the cellular immune response. / • Antigen-MHC complex • Interleukin-2receptors / ,.? T-cell receptor / y Immunoglobulin ) A BCGF receptors [] BCDF receptors
Immunology Today, voL 6, No. 9, 1985
activities. To test this model further we took advantage of the availability of'clonal' neoplastic T4 ÷ cells of patients with a mature T-cell malignancy. Four out of 20 neoplastic T4 + cell populations devoid of helper activity in the P W M system, which failed to produce IL-2 upon P W M stimulation, provided excellent helper activity in the presence of exogenous IL-2 (Miedema et aL, unpublished observations). These data are compatible with the hypothesis that IL-2 production is required for the induction of T4 + cell-derived helper signals for B-cell differentiation. A synergistic effect of IL-2 and other T-cell factors on activatedB cells, however, seems likely since very recently from different laboratories strong evidence was reported that activated B cells express IL-2 receptors ~6-19. Indeed, activated B and T cells express very similar, if not identical, receptors for IL-2 ~7-19. With regard to the functional significance of the expression of IL-2 receptors on B cells, it is now clear that activated, IL-2 receptor-bearing B cells proliferate in response to human recombinant IL2 ~9. The proliferating cells were T3- (< 2 %), Tac + and surface Ig + (> 90%) and thus indeed were B cells 19. Similar data were obtained by others ~5,~s.The question of whether IL-2, apart from BCGF activity, also has B C D F activity has not yet been settled. Preliminary results suggest that this is not the case 18 or that IL-2 has only a marginal BCDF effect on B cells ~5'2°. In summary, the following model for the regulation of human B-cell differentiation and proliferation by T cells can be postulated (Fig. 1): P W M or antigen induce IL-2 production and a rapid enhancement of IL-2 receptor expression on resting T cells. The expression of IL-2 receptors is further regulated by IL-2. This has been demonstrated with peripheral blood T cells 2~'22and with antigen-specific human T-ceU clones 23. This causes, possibly in an autocrine fashion, T-cell proliferation 23 and the IL-2-induced release of helper factors for B-cell growth and differentiation 9 ,2.25. In addition to the induction of T-cell proliferation, IL-2, like BCGF, supports the growth of B cells, once activated 15'18'~9, and induces B C D F release by TR cells. Possibly, BCDF-like molecules can also be induced by an IL-2-independent route, as demonstrated with T cells from a c o m m o n variable immuno-deficiency patient 24. The suppressive effect of T8 + cells on PWM-induced B-cell differentiation occurs not at the level of IL-2 synthesis t~ but most likely at the level of B C G F / B C D F production by helper cells 25. Taken together, the data available at present fit into a model with a pivotal role for IL-2, not only in the regulation of the cellular immune response, but also in the regulation of the humoral immune response.
259
Acknowledgement The authors thank Drs L. A. Aarden and R. W. Sauerwein for stimulating discussions and valuable suggestions. Our work was supported by the Koningin Wilhelmina Fonds/Netherlands Cancer Organization, grant CLB-80~2. Editor's note Since this article was submitted for publication, three recent papers have supported the hypothesis it contains; Nagakawa, T. et al. (1985)J. ImmunoL 134, 3959 Boyd, A. elal. (1985)J. Immunol. 134, 2387 [=~ Lentz, O. etal. (1985)J. Exp. Med. 161, 1225
References 1 2 3 4 5
6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
Waldmann, T. A. and Broder, S. (1982)Adv. Immunol. 32, 1-63 Thomas, Y., Rogozinski, L. and Chess, L. (1983) Immunol. Rev. 74, 113-128 Reinherz, E. L., Meuer, S. C. and Schlossman, S. F. (1983) Immunol. Rev. 74, 83-112 Muraguchi, A. and Fauei, A. S. (1982)J. ImmunoL 129, 1104-1108 Kishimoto, T., Yoshizaki, K. Kimoto, M., Okada, M., Kuritani, T., Kikutani, H., Shimizu, K., Nakagawa, T., Nakagawa, N., Miki, Y., Kishi, H., Fukunaga, K., Yoshikito, T. and Taga, T. (1984)Immunol. Reo. 78, 97 118 Leibson, H.J., Marraek, P. and Kappler, J. (1982)dt. ImmunoL 129, 1398-1402 Parker, D. C. (1982)J. Immunol. 129,469-474 Pure, E , Isackson, P. C., Paetkan, V., Caplan, B., Vitetta, E. S. and Krammer, P. H. (1982)J. ImrnunoL 129, 2420-2425 Inaba, K., Granelli-Piperno, A. and Steinman, R. M. (1983)J. Exp. Med. 158, 2040-2057 Howard, M., Matis, L., Malek, T. R., Seherach, E., Kell, W. Cohen, D., Nakaniski, K. and Paul, W. E. (1983),]. Exp. Med. 158, 2024-2039 Miedema, F., van Oostveen,J. W., Sauerwein, R. W., Terpstra, F. G., Aarden, L.A. and Melief, C.J.M. (1985)Eur.J. ImmunoL 15,107-112 Sauerwein, R. W., van der Meer, W. G.J., Dra~er, A. and Aarden, L. A. Eur. J. ImmunoL in press Leonard, W. J., Depper, J. M., Uchiyama, T., Smith, K. A., Waldmann, T. A. and Greene, W. C. (1982) Nature (London) 300, 267-269 Depper, J. M., Leonard, W.J., Robb, R. J., Waldmann, T. A. and Greene, W. C. (1983),]. Immunol. 131,690-697 Teranishi, T., Hirano, T., Lin, B-H. and Onoue, K. (1984)J. Immunol. 133, 3062-3067 Tsudo, M., Uchiyama, T. and Uchino, H. (1984)J. Exp. Med. 160, 612-617 Waldmann, T. A., Goldman, C. K., Robb, R. J., Depper, J. M., Leonard, W. J., Sharrow, S. O., Bongiovanni, K. F., Korsmeyer, S.J. and Greene, W. C. (1984)J. Exp. Med. 160, 1450-1466 Jung, L. R. L., Hara, T. and Fu, S. M. (1984)J. Exp. Med. 160, 1597-1602 Mingari, M. C., Gerosa, F., Carra, G., Accolla, R. S., Moretta, A., Zubler, R. H., Waldmann, T. A. and Moretta, L. (1984) Nature (London) 312,641-642 Ralph, P., Yeong, G., Welte, K., Mertelsmann, R., Rabin, H., Henderson, L. E., Souza, L. M., Boone, T. C. and Robb, R.J. (1984) ,]. Immunol. 133, 2442-2445 Welte, K., Andreff, M., Platzner, E., Holloway, K., Rubin, B. Y., Moore, M. A. S. and Mertelsman, R. (1984)J. Exp. Med. 160, 1391-1403 Rheem, G. H. and Yeh, N-S. (1984) Science 225,429-430 Meuer, S. C , Hnssey, R. E., Cantrell, D. A., Hodgdon, J. C., Schlossman, S. F., Smith, K. A. and Reinherz, E. L. (1984)Proc. Natl Acad. Sci. USA 81, 1509-1513 Saiki, O., Shimiz,a, M., Saeki, Y., Kishimoto, S. and Kishimoto, T. (1984)J. ImmunoL 133, 1920-1924 Thomas, Y., Sosman,J., Rogozinski, L., Trigoyen, O., Kung, P. C., Gotdstein, G. and Chess, L. (1981)J. ImmunoL 126, 1948 1951