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Whatever its mechanism, M H C gene regulation by IFN suggests that IFN has major biological importance apart from its antiviral activity. First, its influence on the expression of M H C class-II antigens (and our work with K 562) suggest that IFN might be involved in the differentiation of particular cellular systems and might even be considered as a differentiation factor. A particular example of this activity is the ability oflFN-y to strongly enhance class-II antigen expression on macrophages and their capacity for antigen presentation which is Ia restricted 22. Second, IFN-y, one of the lymphokines produced during mixed lymphocyte responses and the mitogenic stimulation of T cells, could be involved in the enhancement of surface levels of M H C antigen which takes place during these processes 23, although our failure to block this enhancement of M H C antigens with monoclonal antibodies to IFN-a,/3 or y (unpublished observations) suggests that factors other than IFN-y are involved. However, the ability of IFN-y to promote the appearance of M H C class-II antigens on cells which do not spontaneously express them, such as skin fibroblasts and endothelial cells, may indicate that the actions of this lymphokine may promote the involvement of these cell types in autoimmune responses z3 and immune processes generally. [=['] Acknowledgements We thank Drs Malissen, Pious, Wiezerbin, for the gifts of monoclonal antibodies B9.12.1, V 1.15. C and recombinant IFN-y. We thank Dr Rubinstein for the gift of purified IFN-a, -ft. We thank D. Hatat and A. Abadie for participating in this wok. Further, we thank Dr Revel for the many helpful discussions and Dr E. Wollman for her help in performing the M L R inhibition assay. F. R O S A
M. FELLOUS Unitd d'Immunoggn~tique Humaine, Institute Pasteur, 25 rue du Dr R oix, 75724 Pans Cedex 15, France.
References 1 Lindahl, P., Leary, P. and Gresser, I. (1973) Proc. NatlAcad. Sci. USA 70, 2785-2788 2 Heron, I., Hokland, M. and Berg, K. (1978) Proc. NatlAcad. Sci. USA 77, 6215-6219 3 Fellous, M., Kamoun, M., Gresser, I. and Bono, R. (1979) Eur. J. Irnmunol. 9, 446-452 4 Wallach, D., FeUous, M. and Revel, M. (1982) Nature (London) 299, 834-836 5 Basham, T. Y., Bourgeade, M. F., Creasey, A. S. and Merigan, T. C. (1982) Proc. Natl Acad. Sci. USA 79, 3265-3268 6 Burrone, O. R. and Milstein, C. (1982) EMBOJ. 1,345-349 7 Fellous, M., Nir, U., Wallach, D., Merlin, G., Rubinstein, M. and Revel, M. (1982) Proe. NatlAcad. Sei USA 79, 3082-3086 8 Pober, J. S., Gimbrone, M. A., Cotran, R. S., Reiss, C. S., Burakoff, S. J., Fiers, W. and Ault, K. A. (1983)J. Exp. Med 157, 1339-1353 9 Steeg, P. S., Moore, R. N., Johnson, H. M. and Oppenheim, J. J. (1982)J. Exp. Med. 156, 1780-1793 10 Wong, G. H. W., Clark-Lewis, I., Mekimm-Bresckin, J. L. and Schrader, J. W. (1982)Proc. Natt Aead. SoL USA 79, 6989-6993 11 Rosa, F., Hatat, D., Abadie, A., Wallaeh, D., Revel, M. and Fellous, M. (1983) EMBOJ. 2, 1585-1589 12 Hirsch, M. R., Wietzerbin, J., Pierres, M. and Goridis, C. (1983) NeuroscieneeLet. 41, 199-204 13 Basham, T. Y. and Merigan, T. C. (1983)J. Immunol. 130, 1492-1493 14 Vireiizier, J. L., Perez, N., Arenzana-Seisdedos, F. and Devos, R. (1984) Eur. J. Immunol. 14, 106-108 15 Wong, G. H. W., Clark-Lewis, I., Harris, A. W. and Schrader, J. W. (1984) Eur. J. ImmunoL 14, 52-56 16 Nakamura, M., Manser, T., Pearson, G. D. N., Daley, M. J. and Gefter, M. L. (1984) Nature (London) 307, 381-382 17 Sutherland, J., Mai?noni, P., Rosa, F., Hatat, D., Wietzerbin, J., Turner, R. A. and Fellous, M. Human Immunology (in press) 18 Pober, J. S., Collins, T., Gimbrone, Jr. M. A., Cotran, R. S., Gitlin, J. D., Fiers, W., Clayberger, C., Krensky, A. M., Burakoff, S. J. and Reiss, C. S. (1983) Nature (London) 305, 726-729 19 Fellous, A., Guinzburg, I. and Littauer, U. Z. (1982) EMBO J. 1, 835-839 20 Rosa, F., Lebouteiller, P. P., Abadie, A., Hatat, D., MishaU, Z., Lemonnier, F. A., Bourrel, D., Lamotte, M., Kalil, J., Jordan, B., and Fellous, M. (1983) Eur. J. Immunol. 13, 495-499 21 Yoshie, O., Schmidt, H., Lengyel, P., Reddy, E. S., Morgan, W. R. and Weissman, S. M. (1984) Proc. NatlAcad. ScL USA 81,649-653 22 Unanue, E. R. (1981)Adv. Immunol. 31, 1 23 McCune, J. M., Humphreys Yoeum, R. R. and Strominger, J. L. (1975) Proc. Natl Acad. Sci. USA 72, 3206-3209 24 Klareskog, L., Forsum, U., Scheynius, A., Kabelitz, D. and Wigzell, H. (1982) Proc. Natl Aead. ScL USA 79, 3632-3636
Major histocompatibility complex molecules as virus receptors Virus receptors have been defined as 'those si~es on the cell surface which recognize or are recognized by virus particles and provide specific points of entry into the cell '1. Many cellular immunologists became interested in such virus receptors after Zinkernagel and Doherty demonstrated that virus-specific cytotoxic T cells were M H C restricted 2. One of the questions originally proposed by these investigators 3 was whether viral antigens need to interact physically with M H C molecules on the cell surface in order to be recognized by T cells (the 'altered-self' hypothesis). Although this proposal is controversial, several studies have provided evidence to indicate that viruses could at least associate with M H C antigens (reviewed in Ref. 4). For example, Schrader et al. 5 demonstrated that patching and capping of H-2 antigens on mouse tumor cells resulted in co-capping of Rauscher leukemia viral antigens. Likewise, capping of the viral determinants resulted in the re-distribution of the tumor cell's H-2 antigens ~. In another study, antibodies to the G protein of vesicular stomatitis virus (VSV) induced re-distribution of H-2 molecules on VSVinfected cells 6. Moreover, both co-capping and electron © 1984,ElsevierSciencePublishersB.V.,Amsterdmn 0167- 4919/84/$02.00
microscopic techniques have demonstrated that vaccinia virus proteins are in close association with M H C molecules on infected cells 7. Finally, a specific association of an adenovirus antigen and M H C molecules has also been reported 8. Although these and other studies have shown that a close physical association could exist between viral and M H C antigens, the vast majority of attempts by many investigators have failed to demonstrate such a physical interaction between M H C molecules and viral antigens on the surface of infected cells.
Perhaps the strongest evidence that M H C molecules could interact with viral antigens and function as true cell surface receptors for a virus was published by Helenius et al. in 19789. These authors demonstrated that human HLA-A and HLA-B and murine H-2K and H-2D M H C antigens could function as receptors for Semliki Forest virus (SFV). SFV attaches to cell surface sites via glycoprotein spikes that extend from the viral membrane. These isolated spikes were shown to inhibit the complement-dependent cytotoxicity of antibodies directed against H-2K and H-2D antigens. In addition,
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isolated H L A - A and H L A - B antigens in lipid vesicles were shown to inhibit the binding of the S F V proteins to h u m a n cell surface membranes. Moreover, complexes between viral spike proteins and M H C molecules (virusreceptor complexes) were isolated from lipid vesicles by affinity chromatography and immunoprecipitation techniques 9. Although this evidence strongly suggests that M H C molecules could function as receptors for SFV, these molecules may not be the only receptors for this virus since cells that lack H-2 can also be infected with
SFV '°. Interest in the concept of MHC molecules as virus receptors may be re-kindled by the results of a recent study by Inada and Mims". This study demonstrated that: (i) the susceptibilityof various murine tissues to infection with lactate dehydrogenase virus (LDV) was directly correlatedwith the percentageof surfacela + cells in the tissue; (2) monoclona] anti-I-A and anti-I-E antibodies could specificallyinhibit LDV infectionof macrophages; and (3) incubation of L D V with solubilized rat Ia antigens (which are structurally homologous to murine I-A and I-E antigens) could inhibit the ability of the virus to infect mouse macrophages. These results strongly indicate that class II M H C molecules could function as receptors for L D V . These observations that M H C molecules can function as receptors for certain viruses raises the following question: do M H C molecules possess a combining site that specifically binds to a viral antigen, or do M H C molecules function passively as ligands for specific recognition molecules on the surface of virus membranes? R e c e n t evidence suggests that the M H C gene family appears to belong to a superfamily of genes that include immunoglobulins, the T-cell receptor, and the i m m u n o g l o b u l i n receptor for I g M and IgA (reviewed in
Refs 12 and 13), all of which are involved in recognition events on the cell m e m b r a n e . This might suggest that M H C molecules could have similarly specific binding functions. However, the evidence to date indicates that only in a very few circumstances can specific, strong interactions be observed between M H C and viral antigens. Thus, in special situations, M H C molecules can act as passive ligands for viral recognition molecules. Additional studies, similar to those of Inada and M i m s with other viruses which show tissue-specific tropisms, could provide more precise molecular definitions of virus receptor molecules, r[] STEVEN JACOBSON AND WILLIAM E. BIDDISON Neuroimmunology Branch, National Institutes of Health, National Institute of Neurological and Communicative Disorders and Stroke, Bethesda, M d 20205, USA.
References ! Meager, A. and Hughes, R. C. (1977) in Receptors and Recognition (Cuatreeasas, P. and Greaves, M. F., eds), pp. 141-196, Chapman and Hall Ltd., London 2 Zinkernagel, R. M. and Doherty, P. C. (1974) Nature (London) 248, 701-702 3 Zinkernagel, R. M. and Doherty, P. C. (1974) Nature (London) 251, 547-548 4 Ciavarra, R. and Forman,J. (1981) Immunol. Rev. 58, 73-94 5 Seharader,J. W., Cunningham, B. A. and Edelman, G. M. (1975)Proc. Natl Acad. Sci. USA 72, 5066-5070 6 Geiger,G., Rosenthal, K. L., Klein,J., Zinkernagel,R. M. and Singer, S. J. (1979) Proc. NatlAcad. Sci. USA 76, 4603-4607 7 Dales, S. and Oldstone, M. B. A. (1982)J. Exp. Med. 156, 1435-1447 8 Kvist, S., Ostberg, L., Persson, H., Philipson, L. and Peterson, P. (1978) Proc. NatlAcad. Sci. USA 75, 5674-5678 9 Helenins, A. Morein, B., Fries, E., Simons, K., Robinson, P., Schirrmaeher, V., Terhorst, C. and Strominger,J. L. (1978) Pore. Natl Acad. Sci. USA 75, 3846-3850 10 Oldstone, M. B. A., Tishon, A., Dutko, F. J., Kennedy, S. I. T., Holland, J. J. and Lampert, P. W. (1980)J. Virol. 34, 256-265 11 Inada, T. and Mims, C. A. (1984) Nature (London) 309, 59-61 12 Williams,A. F. (1984) Nature (London) 308, 12-13 13 Williams,A. F. (1984) Nature (London) 308, 108-109
Immunology Today, vol. 5, No. 9, 1984
Whatever its mechanism, M H C gene regulation by IFN suggests that IFN has major biological importance apart from its antiviral activity. First, its influence on the expression of M H C class-II antigens (and our work with K 562) suggest that IFN might be involved in the differentiation of particular cellular systems and might even be considered as a differentiation factor. A particular example of this activity is the ability oflFN-y to strongly enhance class-II antigen expression on macrophages and their capacity for antigen presentation which is Ia restricted 22. Second, IFN-y, one of the lymphokines produced during mixed lymphocyte responses and the mitogenic stimulation of T cells, could be involved in the enhancement of surface levels of M H C antigen which takes place during these processes 23, although our failure to block this enhancement of M H C antigens with monoclonal antibodies to IFN-a,/3 or y (unpublished observations) suggests that factors other than IFN-y are involved. However, the ability of IFN-y to promote the appearance of M H C class-II antigens on cells which do not spontaneously express them, such as skin fibroblasts and endothelial cells, may indicate that the actions of this lymphokine may promote the involvement of these cell types in autoimmune responses z3 and immune processes generally. [=['] Acknowledgements We thank Drs Malissen, Pious, Wiezerbin, for the gifts of monoclonal antibodies B9.12.1, V 1.15. C and recombinant IFN-y. We thank Dr Rubinstein for the gift of purified IFN-a, -ft. We thank D. Hatat and A. Abadie for participating in this wok. Further, we thank Dr Revel for the many helpful discussions and Dr E. Wollman for her help in performing the M L R inhibition assay. F. R O S A
M. FELLOUS Unitd d'Immunoggn~tique Humaine, Institute Pasteur, 25 rue du Dr R oix, 75724 Pans Cedex 15, France.
References 1 Lindahl, P., Leary, P. and Gresser, I. (1973) Proc. NatlAcad. Sci. USA 70, 2785-2788 2 Heron, I., Hokland, M. and Berg, K. (1978) Proc. NatlAcad. Sci. USA 77, 6215-6219 3 Fellous, M., Kamoun, M., Gresser, I. and Bono, R. (1979) Eur. J. Irnmunol. 9, 446-452 4 Wallach, D., FeUous, M. and Revel, M. (1982) Nature (London) 299, 834-836 5 Basham, T. Y., Bourgeade, M. F., Creasey, A. S. and Merigan, T. C. (1982) Proc. Natl Acad. Sci. USA 79, 3265-3268 6 Burrone, O. R. and Milstein, C. (1982) EMBOJ. 1,345-349 7 Fellous, M., Nir, U., Wallach, D., Merlin, G., Rubinstein, M. and Revel, M. (1982) Proe. NatlAcad. Sei USA 79, 3082-3086 8 Pober, J. S., Gimbrone, M. A., Cotran, R. S., Reiss, C. S., Burakoff, S. J., Fiers, W. and Ault, K. A. (1983)J. Exp. Med 157, 1339-1353 9 Steeg, P. S., Moore, R. N., Johnson, H. M. and Oppenheim, J. J. (1982)J. Exp. Med. 156, 1780-1793 10 Wong, G. H. W., Clark-Lewis, I., Mekimm-Bresckin, J. L. and Schrader, J. W. (1982)Proc. Natt Aead. SoL USA 79, 6989-6993 11 Rosa, F., Hatat, D., Abadie, A., Wallaeh, D., Revel, M. and Fellous, M. (1983) EMBOJ. 2, 1585-1589 12 Hirsch, M. R., Wietzerbin, J., Pierres, M. and Goridis, C. (1983) NeuroscieneeLet. 41, 199-204 13 Basham, T. Y. and Merigan, T. C. (1983)J. Immunol. 130, 1492-1493 14 Vireiizier, J. L., Perez, N., Arenzana-Seisdedos, F. and Devos, R. (1984) Eur. J. Immunol. 14, 106-108 15 Wong, G. H. W., Clark-Lewis, I., Harris, A. W. and Schrader, J. W. (1984) Eur. J. ImmunoL 14, 52-56 16 Nakamura, M., Manser, T., Pearson, G. D. N., Daley, M. J. and Gefter, M. L. (1984) Nature (London) 307, 381-382 17 Sutherland, J., Mai?noni, P., Rosa, F., Hatat, D., Wietzerbin, J., Turner, R. A. and Fellous, M. Human Immunology (in press) 18 Pober, J. S., Collins, T., Gimbrone, Jr. M. A., Cotran, R. S., Gitlin, J. D., Fiers, W., Clayberger, C., Krensky, A. M., Burakoff, S. J. and Reiss, C. S. (1983) Nature (London) 305, 726-729 19 Fellous, A., Guinzburg, I. and Littauer, U. Z. (1982) EMBO J. 1, 835-839 20 Rosa, F., Lebouteiller, P. P., Abadie, A., Hatat, D., MishaU, Z., Lemonnier, F. A., Bourrel, D., Lamotte, M., Kalil, J., Jordan, B., and Fellous, M. (1983) Eur. J. Immunol. 13, 495-499 21 Yoshie, O., Schmidt, H., Lengyel, P., Reddy, E. S., Morgan, W. R. and Weissman, S. M. (1984) Proc. NatlAcad. ScL USA 81,649-653 22 Unanue, E. R. (1981)Adv. Immunol. 31, 1 23 McCune, J. M., Humphreys Yoeum, R. R. and Strominger, J. L. (1975) Proc. Natl Acad. Sci. USA 72, 3206-3209 24 Klareskog, L., Forsum, U., Scheynius, A., Kabelitz, D. and Wigzell, H. (1982) Proc. Natl Aead. ScL USA 79, 3632-3636
Major histocompatibility complex molecules as virus receptors Virus receptors have been defined as 'those si~es on the cell surface which recognize or are recognized by virus particles and provide specific points of entry into the cell '1. Many cellular immunologists became interested in such virus receptors after Zinkernagel and Doherty demonstrated that virus-specific cytotoxic T cells were M H C restricted 2. One of the questions originally proposed by these investigators 3 was whether viral antigens need to interact physically with M H C molecules on the cell surface in order to be recognized by T cells (the 'altered-self' hypothesis). Although this proposal is controversial, several studies have provided evidence to indicate that viruses could at least associate with M H C antigens (reviewed in Ref. 4). For example, Schrader et al. 5 demonstrated that patching and capping of H-2 antigens on mouse tumor cells resulted in co-capping of Rauscher leukemia viral antigens. Likewise, capping of the viral determinants resulted in the re-distribution of the tumor cell's H-2 antigens ~. In another study, antibodies to the G protein of vesicular stomatitis virus (VSV) induced re-distribution of H-2 molecules on VSVinfected cells 6. Moreover, both co-capping and electron © 1984,ElsevierSciencePublishersB.V.,Amsterdmn 0167- 4919/84/$02.00
microscopic techniques have demonstrated that vaccinia virus proteins are in close association with M H C molecules on infected cells 7. Finally, a specific association of an adenovirus antigen and M H C molecules has also been reported 8. Although these and other studies have shown that a close physical association could exist between viral and M H C antigens, the vast majority of attempts by many investigators have failed to demonstrate such a physical interaction between M H C molecules and viral antigens on the surface of infected cells.
Perhaps the strongest evidence that M H C molecules could interact with viral antigens and function as true cell surface receptors for a virus was published by Helenius et al. in 19789. These authors demonstrated that human HLA-A and HLA-B and murine H-2K and H-2D M H C antigens could function as receptors for Semliki Forest virus (SFV). SFV attaches to cell surface sites via glycoprotein spikes that extend from the viral membrane. These isolated spikes were shown to inhibit the complement-dependent cytotoxicity of antibodies directed against H-2K and H-2D antigens. In addition,
263
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isolated H L A - A and H L A - B antigens in lipid vesicles were shown to inhibit the binding of the S F V proteins to h u m a n cell surface membranes. Moreover, complexes between viral spike proteins and M H C molecules (virusreceptor complexes) were isolated from lipid vesicles by affinity chromatography and immunoprecipitation techniques 9. Although this evidence strongly suggests that M H C molecules could function as receptors for SFV, these molecules may not be the only receptors for this virus since cells that lack H-2 can also be infected with
SFV '°. Interest in the concept of MHC molecules as virus receptors may be re-kindled by the results of a recent study by Inada and Mims". This study demonstrated that: (i) the susceptibilityof various murine tissues to infection with lactate dehydrogenase virus (LDV) was directly correlatedwith the percentageof surfacela + cells in the tissue; (2) monoclona] anti-I-A and anti-I-E antibodies could specificallyinhibit LDV infectionof macrophages; and (3) incubation of L D V with solubilized rat Ia antigens (which are structurally homologous to murine I-A and I-E antigens) could inhibit the ability of the virus to infect mouse macrophages. These results strongly indicate that class II M H C molecules could function as receptors for L D V . These observations that M H C molecules can function as receptors for certain viruses raises the following question: do M H C molecules possess a combining site that specifically binds to a viral antigen, or do M H C molecules function passively as ligands for specific recognition molecules on the surface of virus membranes? R e c e n t evidence suggests that the M H C gene family appears to belong to a superfamily of genes that include immunoglobulins, the T-cell receptor, and the i m m u n o g l o b u l i n receptor for I g M and IgA (reviewed in
Refs 12 and 13), all of which are involved in recognition events on the cell m e m b r a n e . This might suggest that M H C molecules could have similarly specific binding functions. However, the evidence to date indicates that only in a very few circumstances can specific, strong interactions be observed between M H C and viral antigens. Thus, in special situations, M H C molecules can act as passive ligands for viral recognition molecules. Additional studies, similar to those of Inada and M i m s with other viruses which show tissue-specific tropisms, could provide more precise molecular definitions of virus receptor molecules, r[] STEVEN JACOBSON AND WILLIAM E. BIDDISON Neuroimmunology Branch, National Institutes of Health, National Institute of Neurological and Communicative Disorders and Stroke, Bethesda, M d 20205, USA.
References ! Meager, A. and Hughes, R. C. (1977) in Receptors and Recognition (Cuatreeasas, P. and Greaves, M. F., eds), pp. 141-196, Chapman and Hall Ltd., London 2 Zinkernagel, R. M. and Doherty, P. C. (1974) Nature (London) 248, 701-702 3 Zinkernagel, R. M. and Doherty, P. C. (1974) Nature (London) 251, 547-548 4 Ciavarra, R. and Forman,J. (1981) Immunol. Rev. 58, 73-94 5 Seharader,J. W., Cunningham, B. A. and Edelman, G. M. (1975)Proc. Natl Acad. Sci. USA 72, 5066-5070 6 Geiger,G., Rosenthal, K. L., Klein,J., Zinkernagel,R. M. and Singer, S. J. (1979) Proc. NatlAcad. Sci. USA 76, 4603-4607 7 Dales, S. and Oldstone, M. B. A. (1982)J. Exp. Med. 156, 1435-1447 8 Kvist, S., Ostberg, L., Persson, H., Philipson, L. and Peterson, P. (1978) Proc. NatlAcad. Sci. USA 75, 5674-5678 9 Helenins, A. Morein, B., Fries, E., Simons, K., Robinson, P., Schirrmaeher, V., Terhorst, C. and Strominger,J. L. (1978) Pore. Natl Acad. Sci. USA 75, 3846-3850 10 Oldstone, M. B. A., Tishon, A., Dutko, F. J., Kennedy, S. I. T., Holland, J. J. and Lampert, P. W. (1980)J. Virol. 34, 256-265 11 Inada, T. and Mims, C. A. (1984) Nature (London) 309, 59-61 12 Williams,A. F. (1984) Nature (London) 308, 12-13 13 Williams,A. F. (1984) Nature (London) 308, 108-109
