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May T3 protect us all
314
Immunology Today, vol. 5, No. 11, 1984
May T3 protect us all Morten Simonsen The long-standing puzzle of the T-cell receptor is finally yielding to intelligent applications of appropriate technologies 1. As a merely passive, though not completely innocent bystander to this exciting new development in an old affair 2, I have been impressed by findings pertaining to the so-called T3 molecules. In fact, this new entity may well present an unexpected new puzzle of more novel features than the clonotypic Ti moiety of the T-cell receptor, which gives, after all, a certain d~'~ vu impression of the now emerging machinery for the generation of diversity3-6. T3 seems to be identical in all T-cell clones and to be common to both major subsets o f T cells. In the model of the T-cell receptor proposed by Reinherz et al. 7, T3 is depicted as a single molecule. This is already known to be wrong. In fact, T3 constitutes a complex of at least three different molecular species s,9. One is a non-glycosylated 20 kd molecule that labels strongly with the hydrophobic reagent 5-iodonaphthyl-l-azide (see Ref. 8). The two others are glycoproteins of 20 kd and 25-28 kd, respectively. Borst et al. 8 suggest that the hydrophobic T3 molecule might be the anchor for the glycosylated T3 species and possibly also for the heterodimer (Ti) that is the carrier of the clonotypic specificity. Notwithstanding the molecular complexities just mentioned, the biological facts remain that were summarized and discussed by Reinherz et al. 7, and which still indicate that T3 is intimately linked with the specific recognition part of the T-cell receptor. The questions are how and to what effect? There is a recent report which may give an important clue. Meuer et al) ° had produced a human M H C class IIrestricted cell clone, RW17C, that could be kept in continuous culture when stimulated with a ragweed antigen presented by autologous antigen-presenting cells and interleukin 2. They also had a monoclonal mouse antibody, anti-Ti4A, that was highly specific for this particular clone o f T cells. Thus, the incubation o f R W 1 7 C cells with anti Ti~A, or with any of several anti T3 monoelonal antibodies co-modulated both the T3 and the Ti structures. In addition - and this is where I think one may hope to find a clue - they found that ~25I-surface labelled and solubilized RW17C cells reacted in immunoprecipitation and SDS-PAGE analysis in a way that implied that the binding of the anti Ti4A antibody dissociated (or prevented) the complex formation with T3. In fact, anti-T3 precipitated both T3 and Ti, while anti-Ti precipitated Ti only. This is precisely the result one would predict on the hypothesis that the T3 complex functions as a natural inhibitor of T-ceU receptors, blocking their specific binding sites from harmful interaction with cross-reacting self determinants. What I am postulating here is that part of the T3 cornInstitute for Experimental Immunology, DK-2100 Copenhagen 0, Denmark. © 1984, Elsevier Science Publishers B.V., Amsterdam 0167 - 4919/84/$02.00
plex has a binding affinity to the Ti molecule which is independent of the fine structure determining the specificity of the latter (e.g. to framework determinants) and yet is close enough to ks antigen-combining site to keep it blocked from interaction with most antigens. However, the blocking is reversible, and the functional effect of it must be a matter of the relative affinities of interaction. Thus it may be postulated that the affinity of T3 to the binding ske (or sites) of Ti sets a threshold which effectively blocks interaction with most or all self-determinants that could otherwise have interacted. However, an ira-
A
T~
Self )
blocked 1 ~.
•.,
.
rnbrane
'~
Ti
Fig. 1. A model of the T-ceU receptor.
The modeldisplaysthe clonotypica andfl chainsofTi as wellas three molecules, a, b, and c, of the T3 complex.The a moleculeis the 20 kd, non N-glyeosylated,membrane-imbedded P9roteinwhich has also a cytoplasmicdomainof ~ 5 000 daltonsin size . It is depictedhere as an anchorage for the two highly N-glycosylatedglycoproteinsb and c, which exert the postulatedblocking.The oligosaccharidemoietiesofb and c amount to roughly 1/3 of the molecular weightss'9and mightwell be crucial to the blocking.
Immunology Today, vol. 5, No. 11, 1984
munogen, e.g. virus protein + self M H C , may transgress the threshold and so may specific antibody to the combining site of Ti (anti Ti4Ain the experiment of Meuer et al. lo), and may consequently displace T3. It is conceivable that this displacement of T3 from the binding region of Ti conveys a signal to some other part of the T3 complex that mediates a necessary step in the triggering ofT-cell activation. Fig. 1 shows a possible relationship to each other of the molecules that constitute the T i - T 3 complex in the membrane. The need for a mechanism to keep T cells out of mischief is probably very real. The reason is that any T-cell clone, brought into action by a foreign immunogen as presented in the context of the individual's own M H C (antigen x + self M H C ) , is likely to cross-react, more or less, with self M H C as modified by self n o n - M H C , of which there are hundreds of different species available. The best example known to me of such a self-self modification, is that of the H-Y induced change in the D b mouse M H C molecule that makes the latter sufficiently like some M H C molecule of the H - 2 s genotype as to render t h e H - 2 w~ female hybrid naturally tolerant of H-Y as presented in the D b context "'~2. This is a particularly impressive example because of the fact that the antigenic similarity required for tolerance induction is presumably greater than for a mere cross-reactivity at the effector cell level. Conformational changes in the M H C molecules, consequent upon interaction with n o n - M H C molecules in the crowded conditions of the membrane space, are in all likelihood responsible for such T-cell cross-reactivity. Besides, with the insulin receptor molecule as a paradigm, it now seems plausible that interactions in the membrane between M H C and n o n - M H C molecules m a y also cause conformational changes in the latter, as
315
suggested by changes in the binding of the physiological ligand (insulin) 13. The proposed self-protective function of T3 may find plenty of challenges in the daily homeostasis of the immune system. It certainly seems to be a simpler means of maintaining natural T-cell tolerance to self, than is an infinitely complicated network of suppressor clones. If true, the system will of course be fallible. Occasionally, even self determinants may transgress the threshold set by T3, and then suppressor clones may be required, or else auto-aggression ensues. I am grateful to Drs M . J . Crurnpton, S. C. Meuer, and C. Terhorst for discussions with them on their respective findings. They are innocent of any mistake of interpretation that I may have made.
References 1 Marrack, P. (1984)Nature (London)309, 310-311 2 Crone, M., Koch, C. and Sirnonsen, M. (1972) Transplant. Rev. 10, 36-56 3 Yanagi, Y., Yoshikai, Y., Legget, K., Clark, S. P., Alexander, I. and Mak, T. W. (1984) Nature (London) 308, 145-149 4 Hedriek, S. M., Cohen, D. I., Nielsen, E. A. and Davis, M. M. (1984) Nature (London) 308, 149-153 5 Chien, Y., Gascogne, R.J., Kavaler, J., Lee, E. L. and Davis, M. M. (1984) Nature (London) 309, 322-326 6 Saito, H., Kranz, D. M., Takagaki, Y., Hayday, A. C., Eisen, H. N. and Tonegawa, S. (1984) Nature (London) 309, 757-762 7 Reinherz, E. L., Meuer, S. C. and Schlossman, S. F. (1983) Immunol. Today 4, 5-8 8 Borst, J., Prendiville, M. A. and Terhorst, C. (1983) Eur. J. Immunol. 13, 576-580 9 Kanellopoulos, J. M., Wigglesworth, N. M., Owen, M. J. and Crumpton, M.J. (1983) EMBOJ. 10, 1807-1814 10 Meuer, S. C., Cooper, D. A., Hodgdon, J. C., Hussey, R. E., Fitzgerald, K. A., Schlossrnan, S. F. and Reinherz, E. L. (1983)Sok,me 222, 1239-1242 11 Simpson, E. (1982) Immunol. Today 3, 97-105 12 Mitchison, N. A. (1981) Seand. J. ImmunoL 14, 631-635 13 Simonsen, M. and Olsson, L. (1984) Prog. Allergy (in press)
Immunology Today, vol. 5, No. 11, 1984
May T3 protect us all Morten Simonsen The long-standing puzzle of the T-cell receptor is finally yielding to intelligent applications of appropriate technologies 1. As a merely passive, though not completely innocent bystander to this exciting new development in an old affair 2, I have been impressed by findings pertaining to the so-called T3 molecules. In fact, this new entity may well present an unexpected new puzzle of more novel features than the clonotypic Ti moiety of the T-cell receptor, which gives, after all, a certain d~'~ vu impression of the now emerging machinery for the generation of diversity3-6. T3 seems to be identical in all T-cell clones and to be common to both major subsets o f T cells. In the model of the T-cell receptor proposed by Reinherz et al. 7, T3 is depicted as a single molecule. This is already known to be wrong. In fact, T3 constitutes a complex of at least three different molecular species s,9. One is a non-glycosylated 20 kd molecule that labels strongly with the hydrophobic reagent 5-iodonaphthyl-l-azide (see Ref. 8). The two others are glycoproteins of 20 kd and 25-28 kd, respectively. Borst et al. 8 suggest that the hydrophobic T3 molecule might be the anchor for the glycosylated T3 species and possibly also for the heterodimer (Ti) that is the carrier of the clonotypic specificity. Notwithstanding the molecular complexities just mentioned, the biological facts remain that were summarized and discussed by Reinherz et al. 7, and which still indicate that T3 is intimately linked with the specific recognition part of the T-cell receptor. The questions are how and to what effect? There is a recent report which may give an important clue. Meuer et al) ° had produced a human M H C class IIrestricted cell clone, RW17C, that could be kept in continuous culture when stimulated with a ragweed antigen presented by autologous antigen-presenting cells and interleukin 2. They also had a monoclonal mouse antibody, anti-Ti4A, that was highly specific for this particular clone o f T cells. Thus, the incubation o f R W 1 7 C cells with anti Ti~A, or with any of several anti T3 monoelonal antibodies co-modulated both the T3 and the Ti structures. In addition - and this is where I think one may hope to find a clue - they found that ~25I-surface labelled and solubilized RW17C cells reacted in immunoprecipitation and SDS-PAGE analysis in a way that implied that the binding of the anti Ti4A antibody dissociated (or prevented) the complex formation with T3. In fact, anti-T3 precipitated both T3 and Ti, while anti-Ti precipitated Ti only. This is precisely the result one would predict on the hypothesis that the T3 complex functions as a natural inhibitor of T-ceU receptors, blocking their specific binding sites from harmful interaction with cross-reacting self determinants. What I am postulating here is that part of the T3 cornInstitute for Experimental Immunology, DK-2100 Copenhagen 0, Denmark. © 1984, Elsevier Science Publishers B.V., Amsterdam 0167 - 4919/84/$02.00
plex has a binding affinity to the Ti molecule which is independent of the fine structure determining the specificity of the latter (e.g. to framework determinants) and yet is close enough to ks antigen-combining site to keep it blocked from interaction with most antigens. However, the blocking is reversible, and the functional effect of it must be a matter of the relative affinities of interaction. Thus it may be postulated that the affinity of T3 to the binding ske (or sites) of Ti sets a threshold which effectively blocks interaction with most or all self-determinants that could otherwise have interacted. However, an ira-
A
T~
Self )
blocked 1 ~.
•.,
.
rnbrane
'~
Ti
Fig. 1. A model of the T-ceU receptor.
The modeldisplaysthe clonotypica andfl chainsofTi as wellas three molecules, a, b, and c, of the T3 complex.The a moleculeis the 20 kd, non N-glyeosylated,membrane-imbedded P9roteinwhich has also a cytoplasmicdomainof ~ 5 000 daltonsin size . It is depictedhere as an anchorage for the two highly N-glycosylatedglycoproteinsb and c, which exert the postulatedblocking.The oligosaccharidemoietiesofb and c amount to roughly 1/3 of the molecular weightss'9and mightwell be crucial to the blocking.
Immunology Today, vol. 5, No. 11, 1984
munogen, e.g. virus protein + self M H C , may transgress the threshold and so may specific antibody to the combining site of Ti (anti Ti4Ain the experiment of Meuer et al. lo), and may consequently displace T3. It is conceivable that this displacement of T3 from the binding region of Ti conveys a signal to some other part of the T3 complex that mediates a necessary step in the triggering ofT-cell activation. Fig. 1 shows a possible relationship to each other of the molecules that constitute the T i - T 3 complex in the membrane. The need for a mechanism to keep T cells out of mischief is probably very real. The reason is that any T-cell clone, brought into action by a foreign immunogen as presented in the context of the individual's own M H C (antigen x + self M H C ) , is likely to cross-react, more or less, with self M H C as modified by self n o n - M H C , of which there are hundreds of different species available. The best example known to me of such a self-self modification, is that of the H-Y induced change in the D b mouse M H C molecule that makes the latter sufficiently like some M H C molecule of the H - 2 s genotype as to render t h e H - 2 w~ female hybrid naturally tolerant of H-Y as presented in the D b context "'~2. This is a particularly impressive example because of the fact that the antigenic similarity required for tolerance induction is presumably greater than for a mere cross-reactivity at the effector cell level. Conformational changes in the M H C molecules, consequent upon interaction with n o n - M H C molecules in the crowded conditions of the membrane space, are in all likelihood responsible for such T-cell cross-reactivity. Besides, with the insulin receptor molecule as a paradigm, it now seems plausible that interactions in the membrane between M H C and n o n - M H C molecules m a y also cause conformational changes in the latter, as
315
suggested by changes in the binding of the physiological ligand (insulin) 13. The proposed self-protective function of T3 may find plenty of challenges in the daily homeostasis of the immune system. It certainly seems to be a simpler means of maintaining natural T-cell tolerance to self, than is an infinitely complicated network of suppressor clones. If true, the system will of course be fallible. Occasionally, even self determinants may transgress the threshold set by T3, and then suppressor clones may be required, or else auto-aggression ensues. I am grateful to Drs M . J . Crurnpton, S. C. Meuer, and C. Terhorst for discussions with them on their respective findings. They are innocent of any mistake of interpretation that I may have made.
References 1 Marrack, P. (1984)Nature (London)309, 310-311 2 Crone, M., Koch, C. and Sirnonsen, M. (1972) Transplant. Rev. 10, 36-56 3 Yanagi, Y., Yoshikai, Y., Legget, K., Clark, S. P., Alexander, I. and Mak, T. W. (1984) Nature (London) 308, 145-149 4 Hedriek, S. M., Cohen, D. I., Nielsen, E. A. and Davis, M. M. (1984) Nature (London) 308, 149-153 5 Chien, Y., Gascogne, R.J., Kavaler, J., Lee, E. L. and Davis, M. M. (1984) Nature (London) 309, 322-326 6 Saito, H., Kranz, D. M., Takagaki, Y., Hayday, A. C., Eisen, H. N. and Tonegawa, S. (1984) Nature (London) 309, 757-762 7 Reinherz, E. L., Meuer, S. C. and Schlossman, S. F. (1983) Immunol. Today 4, 5-8 8 Borst, J., Prendiville, M. A. and Terhorst, C. (1983) Eur. J. Immunol. 13, 576-580 9 Kanellopoulos, J. M., Wigglesworth, N. M., Owen, M. J. and Crumpton, M.J. (1983) EMBOJ. 10, 1807-1814 10 Meuer, S. C., Cooper, D. A., Hodgdon, J. C., Hussey, R. E., Fitzgerald, K. A., Schlossrnan, S. F. and Reinherz, E. L. (1983)Sok,me 222, 1239-1242 11 Simpson, E. (1982) Immunol. Today 3, 97-105 12 Mitchison, N. A. (1981) Seand. J. ImmunoL 14, 631-635 13 Simonsen, M. and Olsson, L. (1984) Prog. Allergy (in press)