Immunology Today, voL 8, No. 5, ! 987
cell types. But exogenous influences arising from nutriments, drugs and microorganisms also modify B-cell reactions, especially when blood or lymph circulation is locally increased when immune reactions occur. In conclusion, it appears that controlled B-cell development or stimulation requires specific cell contacts, exchanges in narrow intercellular spaces of bioactive products and well-defined conditions. If these requirements are lacking hypo- or hyper-sensitivity, autoimmune reactions or uncontrolled proliferation may occur and induce numerous pathological states. Sex-linked agammaglobulinemia for example, may originate in a defective bone marrow environment which stops the evolution of pre-B cells3. Our understanding of the environment necessary for a harmonious immune defense is only at its beginning.
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References 1 Kyewski, B.A. (1986)Immunol. Today 7, 374-379 2 Nossal, GJ.V. (1984)Ann. ImmunoL 135, 195-199 3 Bach, J.F.(1986) Flammanon Med-Sci. Pads, 1986 4 Cooper, M.D., Keamey, J. and Scher, I. (1984) in Fundarnentallmmunology(Paul, W.E., ed) pp. 43-55, Raven Press, New York $ Landreth, S.K. and KincadeP.W. (1984) Dev. Comp. Immunol. 8, 773-790 li Dorshkind.K. (1986) Immunol. Today7, 322-323 7 Muller-Sieburg, C.E., Whithlock, C.A. and Weissman, I.L.
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(1986) 6th International Congress of lmmunol., Toronto p.33 8 Nieuwenhuis, P. (1981)lmmunoL Today2, 104-110 9 van Ewijk, W. and van der Kwast, T.H. (1980) J. Cell. Res. 212,497-508 10 van Rooijen, N., Claassen, E. and Eikelenboom, P. (1986) Immunol. Today 7, 193-196 11 Gallatin, W.M., Weissman, I.L. and Butcher, E.C. (1983) Nature (London) 304, 30-31 12 Tsunoda, R., Terashima, K., Takahashi, K. and Kojima, M. (1978)Acta Pathol. Jpn 28, 53-75 13 Nossal, G.J.V., Ada, G.L., Austin, C.M. and Pye, J. (1965) Immunology 9, 349-356 14 Heinen, E., Lilet-Leclercq, C., Mason, D.Y. etaL (1984)Eur. J. Immunol. 14, 267-273 15 Heinen, E., Radoux, D., Kinet-Denoi~l, C. etal. (1985) Immunology 54, 777-784 16 Lilet-Leclercq, C., Radoux, D., Heinen, E. etaL (1984) J. Immunol. Methods 66, 235-244 17 Wekerle, H. and Ketelsen,V.P. (1980)Nature (London)283, 402-404 18 Corrnann, N., Heinen, E., Kinet-Deno~l, C. etal. (1986) CR. Soc Biol. 180, 218-223 lg Corrnann, N., Lesage, F., Heinen, E. et al. (1986)Immunol. Lett. 14, 29-35 20 Hoefsmit, E.M., Karnperdijk, E.W.A., Hendricks, H.R. etal. (1980) Reticulendothelial Systems I, 417-468 2.1 Mandel, T.E., Phipps, R.P.,Abbot, A. and Tew, J.G. (1980) Immunol. Rev. 53, 30-59 22 Butcher, E.C., Roux, R.V., Coffrnan, R.L. etal. (1982) J. Imrnunol. 129, 2698-2707 23 Kikutani, H., Suemura, M., Owaki, H. et al (1986)J. Exp. Med. 164, 1455-1469
The T-cell antigenreceptorgamma chain and its accomplices The surface protein which has proved to be the elusive T-cell antigen receptor was first identified by immunological methods. T-cell tumors or functional clones were shown to possess a molecule which was idio~pic (i.e. restricted to one clonal population) with the aid of monoclonal antibodies which reacted only with the immunizing cell line 1.2. Immunoprecipitation of the idiotypic molecule showed that it was a disulfide-linked heterodimer. Recombinant DNA technology led to the identification of a gene which was a strong candidate for a receptor component since it was T-cell specific and underwent somatic recombination in T cells in a manner similar to that of immunoglobulin genes in B cells 3.4. This gene was subsequently shown to code for the smaller (13) chain of the idiotypic protein. Several groups set out to identify the other (~ chain) gene. The first candidate reported seemed to have the right properties (T-cell specificity and rearrangement) but was suspe_rt because it lacked glycosylation sii.e~~-. When this gene was not found in all T cells it became clear that it was not the authentic alpha chain gene. But what was it? Without a protein product it was not possible to know whether this gene, now named the ~/chain gene, had any function at all. It might
144
Pathology Department, St Mary's Hospital Medical School, London W21PG, UK
A. W. Boylston have represented a vestigial receptor no longer used in higher animals. After two years as a gene without a protein, the ~/ chain of the T-cell antigen receptor has now been oemonstrated on a range of human and murine T cells 6-8. Surprisingly it is associated with another protein, the 8 chain, whose exact nature is still unknown, and has a greater degree of structural diversity than expected. Finding the ~/ chain protein has required knowing where to look, as well as techniques for preserving its association with the T3 molecular complex. In man the availability of a monoclonal antibody (Mab) called WF-31 which recognizes a determinant on the conventional T-cell receptol ~/13 heterodimer 9 has been an important indicator of ~-expressing cells. Fetal umbilical cord blood cells contain a population of T3-positive, WT-31-negative cells which retain this phenotype in culture and some of the clones derived from these cultures had natural killer activity 1°. Similar cells were present in uncloned T-cell lines established from peripheral blood of two individuals with congenital immunodeficiency syndromes 6. With a crosslinking agent which coupled T3 to the od13 heterodimeH ~ and an anti-T3 Mab a T3-associated protein was demonstrated which reacted with an antibody (~ 1987. Elsevier Publications, Cambridge
0167 - 4919/87/$02.00
Immunology Today, vol. 8, No. 5, 1987
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raised to a peptide whose sequence was predicted from effective affinity of T cells for targets by stabilizing the the nucleic acid sequence of the ~/chain gene. This ~/ interaction between the antigen receptor and MHCchain protein has a mol. wt of 55kDa and is noncovalentcomplexed antigen. Perhaps the ~ protein interacts with ly linked to a second molecule (proposed name 8 protein) a molecule present on foetal cells which is different from with a mol. wt of 40kDa, and to the expected T3 conventional MHC and helps the interaction between ~/ components. A second T3-associated ~/chain complex chains and their target. Persistence of such lymphocytes composed of subunits of 62kd and 44kd has also been into post-natal life might reflect the need to recognize a described 7. A cloned thymocyte line with the phenotype few cells of foetal type which last into adult life. T3 +, T4-, TS- was the source of this molecule and the Cells with a double-negative phenotype are the majorT3 complex was functional since cytotoxicity, proliferaity of lymphoid cells in the mouse foetal thymus at day tion and interleukin 2 (IL-2) secretion could be induced 16/17 after fertilization. They may be precursors ef cells with anti-T3 Mab. The ahti-~/chain antibody reacted with exprassing conventional antigen receptors8. These cells the 44kDa component. The 62kDa protein, therefore, are rcn in ~/chain messenger (m) RNA and 13chain mRNA may be either the 8 equivalent or a different T3/~/- but have little (~ chain message. When they are cultivated associated subunit. in vitro the 13 mRNA message disappears but the ~/ Human I/ proteins are also found on T3 ÷, WT-31message and protein production persists, indicating that clones from foetal and normal adult blood which have a sw,tcn is not inevitable. natural killer activity ~2-1s and a leukemic line PEERS of It is not yet clear whether ~/chain-expressing lymphothe same membrane phenotype 13.16. Strikingly, several cytes are true T cells or T-cell precursors or whether they different patterns of ~/ chain use are revealed. PEERS represent a distinct cell lineage which does not require expresses a noncovalently bonded ~/chain which may or thymus processing The presence of high levels of functional ~/mRNA in athymic nude mice, coupled with the may not be associated with a 38 kDa 8 chain. Five of the virtual absence of a or 13 message, argues that the normal clones have disulfide-linked ~/chain dimers with different molecular weights which seem to represent thymus is not necessary for the development of these cells2°. However, conventional T cells do sometimes different glycosylated forms of the same polypeptide. express functional ~ mRNA, even though they do not But that is not all the complexity. Burst has shown that make the protein. This seems to occur in cells which have three independently isolated clones express a */ chain disulfide-bonded to a non-~/ peptide which is slightly been activated by alloantigenic stimuli rather than conventional mitogens, which suggests that the responding larger than the ~ chain itselP 2. And just to further cloud cells may represent a previously unrecognised the picture, Brenner has shown that two of his clones subsets.21.22. However, the ~/message found in mature have ~/chains with peptide backbones of very different lymphocytes seems to code for a molecule which has no molecular weights (31 and 40 kDa) 13. glycosylation sites while the molecule encoded within Some of this diversity may be explained by the finding cells from the foetal thymus has at least five such sites. that PEERSseems to have more than one way of building the second exon of the ~/chain constant region ~6. Cells The foetal cell line may therefore not be ancestral to the mature receptor-expressing population 23. may be able to use one, two, or three very similar 48 __:_ J. L A ~luwuug.- ,,UdW studies suggested that there rw.gmLu~ I~,uo~ r~e~ rvo,, . ~ - ' J . segments ;~ I I I +~-'~^-LGII I U C I I I ~'^+ U E I . V.V.E.E.I . . I +~^ El I E ::"+ I I I ~ 1 ~11 I U "~:'~ ILl I I I U ""~ only one variable region gene associated with the ~/chain constant region exons. These segments have potential constant region, it now appears that there is a significant glycosylation sites, so that size polymorphism of both peptide backbone and fully mature cell-surface protein is diversity in both humans and mice24-26. Three functional murine and five functional human V genes have been possible. described. The degree of genetic complexity thus The murine ~/chain has been described on a subset of thymoc~es which has the phenotype T3 +, T4-, T8- (the approximates that of mouse immunoglobulin k light 'double negatives') s. This rare subset accounts for less chains which can form perfectly adequate antibodies to a range of antigens despite a limited V gene repertoire27. than 5% of thymoc~es but is present in human Certain shared features among mouse and human ~/ peripheral blood and represents essentially all of the T3 +, Wl-31- cells (up to 10% of peripheral blood T cells)17. chain-expressing cells strongly suggest that this is a Precipitation of the T3-associated molecules from these distinct and unique cell population. They all express T3 without a conventional od13 heterodimer. All the cells cells was accomplished by lysing the cells in digitonin, detected in vivo lack CD4 and CD8 molecules. The cell which does not disrupt the noncovalent association type is prominent in foetal life but persists into adultbetween T3 and other components t 8. Two proteins were identified, a 35kDa band which reacts with an anti-~/ hood, and they are unusually prominent in some types of immunodeficiency. Thus, the stage is set for a detailed antiserum and a 45kDa band which does not. Thus a 'a' investigation of this population and its role in the mileu chain is present on mouse cells, as well as human cells. What is the function of the 'a' chain (or chains, if interieur. there really is more than one ~,-associated, non-CD3 References component)? One possibility is that it/they may be the 1 Allison, J.P.,Maclntyre, B.W. and Block, D. (1982) ~/-using cell's equivalent of the CD4 and CD8 antigens. J. 129, 2293 All WT-31- CD3 + human cells detected in vivo lack 2 Immunol. Meuer, S.C., Fitzgerald,K.A., Hussey,R.E.etaL (1983)J. Exp. both these molecules 1 7 ,1 9 . As mentioned above, the Med. 157, 705 mouse equivalent is also 'double negative'. A few WT3 Hedrick, S.M., Cohen, D.I., Nielsen, E.A. and Davis, M.M. 31- clones have expressed CD8 but perhaps as a con(1984) Nature (London) 308, 149 sequence of in-vitro cultivation ~°. The CD4 and CD8 4 Yanagi, Y., Yoshikai,Y., Leggett, K. etal. (1984)Nature molecules are thought to guide normal T cells by in(London) 308, 145 5 Saito, H., Kranz, D.M., Takagaki,Y. eta/. (1984)Nature teracting with class II or class I histocompatibility mole(London) 309, 757 cules expressed on other cells. They may increase the
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Immunology Today, vol. 8, No 5, 1987
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6 Brenner,M.B., McLean.J.. Dialynas,L~.etaL (1986)Nature (London) 322, 145 7 Bank, I., Depino, R.A., Brenner, M.B. etal. (1986)Nature (London) 322, i 79 8 Lew, A.M., Pardoll, DM., Maloy, W.L. etal. (1986)Science 234, 1401 9 Spits, H., Borst,J., Tax, W.T. etal. (1985)J. Imrnuno!. 135, 1922 10 Nowill, A., Moingeon, P., Ythier, A. etal. (1986)J. Exp. Med. 163, 1601 11 Brenner,M.B., Tiowbridg~, I.S.and Strominger, J.L. (1985) Cell40, 183 12 Borst,J., van de Griend, R.J.,van Oostvein, J.W. etal. (1987) Nature (London) 325, 683 13 Brenner,M.B., McLean,J., Scheft, H. etal. (1987)Nature (London) 325, 689 14 Moingeon, P., Jitsukawa, S., Faure, F. etal. (1987)Nature (London) 325, 723 lS Alarcon B., de Vries, J.E.,Pettey, C. etal. (1987) Proc Natl Acad. Sci. USA (in press) 16 Littman, D.R., Newton, M, Cromrnie, D. etal. (1987)Nature
(London) 326, 85 17 Lanier, L.L.and Weiss, A. (1986) Nature (London) 324, 268 18 Oettgen, H.C., Petty, C.L, Maloy, W.L and Terhorst, C. (1986) Nature (London) 320, 272 19 Weiss, A., Newton, M. and Crommie, D. (1986) Proc. Natl Acad. Sci. USA 83, 6998 20 Yoshikai, Y., Reis,M.D. and Mak, T.W. (1986)Nature (London) 324, 482 21 Raulet, D.H., Garman, R.D., Saito, H. and Tonegawa, S. (1985) Nature (London) 314, 103 22 Jones, B., Mjolsness, S., Janeway, Jr, C. and Hayday,A.C. (1986) Nature (London) 323, 635 23 Pardoll, D.M., Fowlkes, B.J., Bluestone,J.A. etal. (1987) Nature (London) 326, 79 24 Garman, R.D., Doherty, P.J.and Raulet, D.H. (1986) Cell45, 733 2S LeFranc,M.P., Forster, A., Baer, R. etal. (1986) Cell 45, 237 26 Helig, J.S. and Tonegawa, S. (1986) Nature (London) 322, 836 27 Eisen,H.N. and Reilly, E.B.(1985)Annu. Rev. Irnmunol. 3, 337
Macroglia: neural cells responsiveto lymphokinesand growth fadors In neural tissue, neurons are supported mechanically and metabolical(y by populations of glial cells which, in mammalian brain, may outnumber neurons tenfold. There is growing evidence that glial cells do more than simply maintain the glue-like function their name implies. In this article, Jean Merrill discussesthe two major glial populations in the CNS, astrocytes and oligodendrocytes, and shows that they both respond to, and that astrocvtes _synthesiz_e,~ v~rip~ nf lurnnhnl,ln,,c =nrt other growth factors. These and related findings indicate that the nervoussystem is by no means as inaccessible to immune reactivity as once was thought. Glial cells in the central nervous system (CNS) consist of microglia, a phagocytic cell type, and macroglia which are grouped into three classes: astrocytes, oligodendrocytes and ependymal cells. Macroglia provide neurons with metabolic support and modulate their functions. Recent investigations have disclosed that macroglia respond to and synthesize a considerable number of soluble factors, several of which are either immunologically active or resemble known lymphokines. This is just one of several kinds of interactions and relationships that have now been established between the cells of the CNS and those involved in immune responses. Certain surface antigens such as Thyl (Ref. 1), myelin-associated glycoprotein 2, and class I and II major histocompatibility (MHC) antigens 3.4 are shared by lymphocytes and brain cells. These may play a role in cell-cell adhesion and/or interaction during embryogenesis, neonatal development, trauma and disease. Neural cells such as astrocytes can be activated during trauma and disease and subsequently mimic blood-borne monocytes
146
Departmentof Neurology, Universityof Califomb at Los Angeles, Los Angeles, CA 90024, USA
Jean E. Merrill or macrophages both phenotypically and functionally s-12. Astrocytes respond to macrophagederived or microgiia-derived factors 13.14 and oligodendrocytes respond to T-cell-derived lymphokines 1°.1s-~7. Under certain circumstances leukocytes traffic in and out of the CNS. Bone marrow-derived monocytes 18-2° and activated T lymphocytes 11.21 find their way into the brain parenchyma even when the blood-brain barrier is intact. Furthermore, astrocytes 21 and Schwann cells22 (a glial cell type in the peripheral nervous system) can be induced by interferon gamma to present autoantigens, including endogenous myelin basic protein (MBP)22. The mature brain is not static. It contains bipotential precursor cells as well as mature glial cells capable of undergoing proliferation and further differentiation in response to the stimuli of injury or disease 23.24. After trauma, endogenous growth-promoting factors of the CNS initiate and facilitate the wound-healing mechanism. They may also act sequentially or in synergy with exogenous growth factors and lymphokines derived from inflammatory lymphocytic infiltrates. In this review I will discuss the plasticity of macroglial cells and their response to growth factors and lymphokines in the CNS. Glial cell lineage Virchow 2s first described macroglia as non-neuronal cells derived from neuroectoderm. However, Golgi staining, introduced in 1873, was the first technique to allow a distinction to be made between the primitive glial precursor, the spongioblast, and the neuroblast which gave rise to neurons 26. Cajal noted that neuroblasts arose before the astroblasts (which gave rise to astrocytes) and before a third cell which was later elucidated by del Rio Hortega 27 as the oligodendrocyte. A separate (~ 1987. ElsevierPublicaTions,Camoridge 0167-4919/87150200
cell types. But exogenous influences arising from nutriments, drugs and microorganisms also modify B-cell reactions, especially when blood or lymph circulation is locally increased when immune reactions occur. In conclusion, it appears that controlled B-cell development or stimulation requires specific cell contacts, exchanges in narrow intercellular spaces of bioactive products and well-defined conditions. If these requirements are lacking hypo- or hyper-sensitivity, autoimmune reactions or uncontrolled proliferation may occur and induce numerous pathological states. Sex-linked agammaglobulinemia for example, may originate in a defective bone marrow environment which stops the evolution of pre-B cells3. Our understanding of the environment necessary for a harmonious immune defense is only at its beginning.
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References 1 Kyewski, B.A. (1986)Immunol. Today 7, 374-379 2 Nossal, GJ.V. (1984)Ann. ImmunoL 135, 195-199 3 Bach, J.F.(1986) Flammanon Med-Sci. Pads, 1986 4 Cooper, M.D., Keamey, J. and Scher, I. (1984) in Fundarnentallmmunology(Paul, W.E., ed) pp. 43-55, Raven Press, New York $ Landreth, S.K. and KincadeP.W. (1984) Dev. Comp. Immunol. 8, 773-790 li Dorshkind.K. (1986) Immunol. Today7, 322-323 7 Muller-Sieburg, C.E., Whithlock, C.A. and Weissman, I.L.
l
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i
(1986) 6th International Congress of lmmunol., Toronto p.33 8 Nieuwenhuis, P. (1981)lmmunoL Today2, 104-110 9 van Ewijk, W. and van der Kwast, T.H. (1980) J. Cell. Res. 212,497-508 10 van Rooijen, N., Claassen, E. and Eikelenboom, P. (1986) Immunol. Today 7, 193-196 11 Gallatin, W.M., Weissman, I.L. and Butcher, E.C. (1983) Nature (London) 304, 30-31 12 Tsunoda, R., Terashima, K., Takahashi, K. and Kojima, M. (1978)Acta Pathol. Jpn 28, 53-75 13 Nossal, G.J.V., Ada, G.L., Austin, C.M. and Pye, J. (1965) Immunology 9, 349-356 14 Heinen, E., Lilet-Leclercq, C., Mason, D.Y. etaL (1984)Eur. J. Immunol. 14, 267-273 15 Heinen, E., Radoux, D., Kinet-Denoi~l, C. etal. (1985) Immunology 54, 777-784 16 Lilet-Leclercq, C., Radoux, D., Heinen, E. etaL (1984) J. Immunol. Methods 66, 235-244 17 Wekerle, H. and Ketelsen,V.P. (1980)Nature (London)283, 402-404 18 Corrnann, N., Heinen, E., Kinet-Deno~l, C. etal. (1986) CR. Soc Biol. 180, 218-223 lg Corrnann, N., Lesage, F., Heinen, E. et al. (1986)Immunol. Lett. 14, 29-35 20 Hoefsmit, E.M., Karnperdijk, E.W.A., Hendricks, H.R. etal. (1980) Reticulendothelial Systems I, 417-468 2.1 Mandel, T.E., Phipps, R.P.,Abbot, A. and Tew, J.G. (1980) Immunol. Rev. 53, 30-59 22 Butcher, E.C., Roux, R.V., Coffrnan, R.L. etal. (1982) J. Imrnunol. 129, 2698-2707 23 Kikutani, H., Suemura, M., Owaki, H. et al (1986)J. Exp. Med. 164, 1455-1469
The T-cell antigenreceptorgamma chain and its accomplices The surface protein which has proved to be the elusive T-cell antigen receptor was first identified by immunological methods. T-cell tumors or functional clones were shown to possess a molecule which was idio~pic (i.e. restricted to one clonal population) with the aid of monoclonal antibodies which reacted only with the immunizing cell line 1.2. Immunoprecipitation of the idiotypic molecule showed that it was a disulfide-linked heterodimer. Recombinant DNA technology led to the identification of a gene which was a strong candidate for a receptor component since it was T-cell specific and underwent somatic recombination in T cells in a manner similar to that of immunoglobulin genes in B cells 3.4. This gene was subsequently shown to code for the smaller (13) chain of the idiotypic protein. Several groups set out to identify the other (~ chain) gene. The first candidate reported seemed to have the right properties (T-cell specificity and rearrangement) but was suspe_rt because it lacked glycosylation sii.e~~-. When this gene was not found in all T cells it became clear that it was not the authentic alpha chain gene. But what was it? Without a protein product it was not possible to know whether this gene, now named the ~/chain gene, had any function at all. It might
144
Pathology Department, St Mary's Hospital Medical School, London W21PG, UK
A. W. Boylston have represented a vestigial receptor no longer used in higher animals. After two years as a gene without a protein, the ~/ chain of the T-cell antigen receptor has now been oemonstrated on a range of human and murine T cells 6-8. Surprisingly it is associated with another protein, the 8 chain, whose exact nature is still unknown, and has a greater degree of structural diversity than expected. Finding the ~/ chain protein has required knowing where to look, as well as techniques for preserving its association with the T3 molecular complex. In man the availability of a monoclonal antibody (Mab) called WF-31 which recognizes a determinant on the conventional T-cell receptol ~/13 heterodimer 9 has been an important indicator of ~-expressing cells. Fetal umbilical cord blood cells contain a population of T3-positive, WT-31-negative cells which retain this phenotype in culture and some of the clones derived from these cultures had natural killer activity 1°. Similar cells were present in uncloned T-cell lines established from peripheral blood of two individuals with congenital immunodeficiency syndromes 6. With a crosslinking agent which coupled T3 to the od13 heterodimeH ~ and an anti-T3 Mab a T3-associated protein was demonstrated which reacted with an antibody (~ 1987. Elsevier Publications, Cambridge
0167 - 4919/87/$02.00
Immunology Today, vol. 8, No. 5, 1987
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raised to a peptide whose sequence was predicted from effective affinity of T cells for targets by stabilizing the the nucleic acid sequence of the ~/chain gene. This ~/ interaction between the antigen receptor and MHCchain protein has a mol. wt of 55kDa and is noncovalentcomplexed antigen. Perhaps the ~ protein interacts with ly linked to a second molecule (proposed name 8 protein) a molecule present on foetal cells which is different from with a mol. wt of 40kDa, and to the expected T3 conventional MHC and helps the interaction between ~/ components. A second T3-associated ~/chain complex chains and their target. Persistence of such lymphocytes composed of subunits of 62kd and 44kd has also been into post-natal life might reflect the need to recognize a described 7. A cloned thymocyte line with the phenotype few cells of foetal type which last into adult life. T3 +, T4-, TS- was the source of this molecule and the Cells with a double-negative phenotype are the majorT3 complex was functional since cytotoxicity, proliferaity of lymphoid cells in the mouse foetal thymus at day tion and interleukin 2 (IL-2) secretion could be induced 16/17 after fertilization. They may be precursors ef cells with anti-T3 Mab. The ahti-~/chain antibody reacted with exprassing conventional antigen receptors8. These cells the 44kDa component. The 62kDa protein, therefore, are rcn in ~/chain messenger (m) RNA and 13chain mRNA may be either the 8 equivalent or a different T3/~/- but have little (~ chain message. When they are cultivated associated subunit. in vitro the 13 mRNA message disappears but the ~/ Human I/ proteins are also found on T3 ÷, WT-31message and protein production persists, indicating that clones from foetal and normal adult blood which have a sw,tcn is not inevitable. natural killer activity ~2-1s and a leukemic line PEERS of It is not yet clear whether ~/chain-expressing lymphothe same membrane phenotype 13.16. Strikingly, several cytes are true T cells or T-cell precursors or whether they different patterns of ~/ chain use are revealed. PEERS represent a distinct cell lineage which does not require expresses a noncovalently bonded ~/chain which may or thymus processing The presence of high levels of functional ~/mRNA in athymic nude mice, coupled with the may not be associated with a 38 kDa 8 chain. Five of the virtual absence of a or 13 message, argues that the normal clones have disulfide-linked ~/chain dimers with different molecular weights which seem to represent thymus is not necessary for the development of these cells2°. However, conventional T cells do sometimes different glycosylated forms of the same polypeptide. express functional ~ mRNA, even though they do not But that is not all the complexity. Burst has shown that make the protein. This seems to occur in cells which have three independently isolated clones express a */ chain disulfide-bonded to a non-~/ peptide which is slightly been activated by alloantigenic stimuli rather than conventional mitogens, which suggests that the responding larger than the ~ chain itselP 2. And just to further cloud cells may represent a previously unrecognised the picture, Brenner has shown that two of his clones subsets.21.22. However, the ~/message found in mature have ~/chains with peptide backbones of very different lymphocytes seems to code for a molecule which has no molecular weights (31 and 40 kDa) 13. glycosylation sites while the molecule encoded within Some of this diversity may be explained by the finding cells from the foetal thymus has at least five such sites. that PEERSseems to have more than one way of building the second exon of the ~/chain constant region ~6. Cells The foetal cell line may therefore not be ancestral to the mature receptor-expressing population 23. may be able to use one, two, or three very similar 48 __:_ J. L A ~luwuug.- ,,UdW studies suggested that there rw.gmLu~ I~,uo~ r~e~ rvo,, . ~ - ' J . segments ;~ I I I +~-'~^-LGII I U C I I I ~'^+ U E I . V.V.E.E.I . . I +~^ El I E ::"+ I I I ~ 1 ~11 I U "~:'~ ILl I I I U ""~ only one variable region gene associated with the ~/chain constant region exons. These segments have potential constant region, it now appears that there is a significant glycosylation sites, so that size polymorphism of both peptide backbone and fully mature cell-surface protein is diversity in both humans and mice24-26. Three functional murine and five functional human V genes have been possible. described. The degree of genetic complexity thus The murine ~/chain has been described on a subset of thymoc~es which has the phenotype T3 +, T4-, T8- (the approximates that of mouse immunoglobulin k light 'double negatives') s. This rare subset accounts for less chains which can form perfectly adequate antibodies to a range of antigens despite a limited V gene repertoire27. than 5% of thymoc~es but is present in human Certain shared features among mouse and human ~/ peripheral blood and represents essentially all of the T3 +, Wl-31- cells (up to 10% of peripheral blood T cells)17. chain-expressing cells strongly suggest that this is a Precipitation of the T3-associated molecules from these distinct and unique cell population. They all express T3 without a conventional od13 heterodimer. All the cells cells was accomplished by lysing the cells in digitonin, detected in vivo lack CD4 and CD8 molecules. The cell which does not disrupt the noncovalent association type is prominent in foetal life but persists into adultbetween T3 and other components t 8. Two proteins were identified, a 35kDa band which reacts with an anti-~/ hood, and they are unusually prominent in some types of immunodeficiency. Thus, the stage is set for a detailed antiserum and a 45kDa band which does not. Thus a 'a' investigation of this population and its role in the mileu chain is present on mouse cells, as well as human cells. What is the function of the 'a' chain (or chains, if interieur. there really is more than one ~,-associated, non-CD3 References component)? One possibility is that it/they may be the 1 Allison, J.P.,Maclntyre, B.W. and Block, D. (1982) ~/-using cell's equivalent of the CD4 and CD8 antigens. J. 129, 2293 All WT-31- CD3 + human cells detected in vivo lack 2 Immunol. Meuer, S.C., Fitzgerald,K.A., Hussey,R.E.etaL (1983)J. Exp. both these molecules 1 7 ,1 9 . As mentioned above, the Med. 157, 705 mouse equivalent is also 'double negative'. A few WT3 Hedrick, S.M., Cohen, D.I., Nielsen, E.A. and Davis, M.M. 31- clones have expressed CD8 but perhaps as a con(1984) Nature (London) 308, 149 sequence of in-vitro cultivation ~°. The CD4 and CD8 4 Yanagi, Y., Yoshikai,Y., Leggett, K. etal. (1984)Nature molecules are thought to guide normal T cells by in(London) 308, 145 5 Saito, H., Kranz, D.M., Takagaki,Y. eta/. (1984)Nature teracting with class II or class I histocompatibility mole(London) 309, 757 cules expressed on other cells. They may increase the
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6 Brenner,M.B., McLean.J.. Dialynas,L~.etaL (1986)Nature (London) 322, 145 7 Bank, I., Depino, R.A., Brenner, M.B. etal. (1986)Nature (London) 322, i 79 8 Lew, A.M., Pardoll, DM., Maloy, W.L. etal. (1986)Science 234, 1401 9 Spits, H., Borst,J., Tax, W.T. etal. (1985)J. Imrnuno!. 135, 1922 10 Nowill, A., Moingeon, P., Ythier, A. etal. (1986)J. Exp. Med. 163, 1601 11 Brenner,M.B., Tiowbridg~, I.S.and Strominger, J.L. (1985) Cell40, 183 12 Borst,J., van de Griend, R.J.,van Oostvein, J.W. etal. (1987) Nature (London) 325, 683 13 Brenner,M.B., McLean,J., Scheft, H. etal. (1987)Nature (London) 325, 689 14 Moingeon, P., Jitsukawa, S., Faure, F. etal. (1987)Nature (London) 325, 723 lS Alarcon B., de Vries, J.E.,Pettey, C. etal. (1987) Proc Natl Acad. Sci. USA (in press) 16 Littman, D.R., Newton, M, Cromrnie, D. etal. (1987)Nature
(London) 326, 85 17 Lanier, L.L.and Weiss, A. (1986) Nature (London) 324, 268 18 Oettgen, H.C., Petty, C.L, Maloy, W.L and Terhorst, C. (1986) Nature (London) 320, 272 19 Weiss, A., Newton, M. and Crommie, D. (1986) Proc. Natl Acad. Sci. USA 83, 6998 20 Yoshikai, Y., Reis,M.D. and Mak, T.W. (1986)Nature (London) 324, 482 21 Raulet, D.H., Garman, R.D., Saito, H. and Tonegawa, S. (1985) Nature (London) 314, 103 22 Jones, B., Mjolsness, S., Janeway, Jr, C. and Hayday,A.C. (1986) Nature (London) 323, 635 23 Pardoll, D.M., Fowlkes, B.J., Bluestone,J.A. etal. (1987) Nature (London) 326, 79 24 Garman, R.D., Doherty, P.J.and Raulet, D.H. (1986) Cell45, 733 2S LeFranc,M.P., Forster, A., Baer, R. etal. (1986) Cell 45, 237 26 Helig, J.S. and Tonegawa, S. (1986) Nature (London) 322, 836 27 Eisen,H.N. and Reilly, E.B.(1985)Annu. Rev. Irnmunol. 3, 337
Macroglia: neural cells responsiveto lymphokinesand growth fadors In neural tissue, neurons are supported mechanically and metabolical(y by populations of glial cells which, in mammalian brain, may outnumber neurons tenfold. There is growing evidence that glial cells do more than simply maintain the glue-like function their name implies. In this article, Jean Merrill discussesthe two major glial populations in the CNS, astrocytes and oligodendrocytes, and shows that they both respond to, and that astrocvtes _synthesiz_e,~ v~rip~ nf lurnnhnl,ln,,c =nrt other growth factors. These and related findings indicate that the nervoussystem is by no means as inaccessible to immune reactivity as once was thought. Glial cells in the central nervous system (CNS) consist of microglia, a phagocytic cell type, and macroglia which are grouped into three classes: astrocytes, oligodendrocytes and ependymal cells. Macroglia provide neurons with metabolic support and modulate their functions. Recent investigations have disclosed that macroglia respond to and synthesize a considerable number of soluble factors, several of which are either immunologically active or resemble known lymphokines. This is just one of several kinds of interactions and relationships that have now been established between the cells of the CNS and those involved in immune responses. Certain surface antigens such as Thyl (Ref. 1), myelin-associated glycoprotein 2, and class I and II major histocompatibility (MHC) antigens 3.4 are shared by lymphocytes and brain cells. These may play a role in cell-cell adhesion and/or interaction during embryogenesis, neonatal development, trauma and disease. Neural cells such as astrocytes can be activated during trauma and disease and subsequently mimic blood-borne monocytes
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Departmentof Neurology, Universityof Califomb at Los Angeles, Los Angeles, CA 90024, USA
Jean E. Merrill or macrophages both phenotypically and functionally s-12. Astrocytes respond to macrophagederived or microgiia-derived factors 13.14 and oligodendrocytes respond to T-cell-derived lymphokines 1°.1s-~7. Under certain circumstances leukocytes traffic in and out of the CNS. Bone marrow-derived monocytes 18-2° and activated T lymphocytes 11.21 find their way into the brain parenchyma even when the blood-brain barrier is intact. Furthermore, astrocytes 21 and Schwann cells22 (a glial cell type in the peripheral nervous system) can be induced by interferon gamma to present autoantigens, including endogenous myelin basic protein (MBP)22. The mature brain is not static. It contains bipotential precursor cells as well as mature glial cells capable of undergoing proliferation and further differentiation in response to the stimuli of injury or disease 23.24. After trauma, endogenous growth-promoting factors of the CNS initiate and facilitate the wound-healing mechanism. They may also act sequentially or in synergy with exogenous growth factors and lymphokines derived from inflammatory lymphocytic infiltrates. In this review I will discuss the plasticity of macroglial cells and their response to growth factors and lymphokines in the CNS. Glial cell lineage Virchow 2s first described macroglia as non-neuronal cells derived from neuroectoderm. However, Golgi staining, introduced in 1873, was the first technique to allow a distinction to be made between the primitive glial precursor, the spongioblast, and the neuroblast which gave rise to neurons 26. Cajal noted that neuroblasts arose before the astroblasts (which gave rise to astrocytes) and before a third cell which was later elucidated by del Rio Hortega 27 as the oligodendrocyte. A separate (~ 1987. ElsevierPublicaTions,Camoridge 0167-4919/87150200
