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Self superantigens?
Cell, Vol. 63, 659-661, November16, 1990,Copyright0 1990 by Cell Press
M inireview
Self Superantigens?
Charles A. Janeway, Jr. Section of lmmunobiology Yale University School of Medicine Howard Hughes Medical institute New Haven, Connecticut 06510
The term superantigen has been proposed by White et al. (1989) to describe several structures that stimulate T lymphocytes by a novel mechanism. Superantigens are distinguished from conventional antigens by the high frequency of responding T cells (-50/o-25%); they are also distinguished from polyclonal T cell mitogens, such as concanavalin A, by the fact that the stimulus activates the T cell by binding a specific site in the variable portion of the I3 chain of the specific T cell antigen receptor (TCR). At present, there are two main categories of superantigens with closely similar properties: the toxic molecules produced by certain bacteria and the still-uncharacterized products of several unlinked genetic loci in the mouse, the best known of which are called M/s (minor lymphocyte stimulating). Mice that express certain self superantigens eliminate those T cells whose TCR p chain would confer reactivity to the self superantigens (Kappler et al., 1988; MacDonald et al., 1988). Kappler and Marrack have shown that it is the T cell response to bacterial toxins that actually causes pathology and have speculated that the mouse developed self superantigens to eliminate these T cells through clonal deletion (Kappler et al., 1989). However, Cazenave et al. (1990) present data that they use to argue against this hypothesis of convergent evolution. This raises several interesting questions: How do superantigens activate T cells? If M/s did not evolve to delete toxin-responsive T cells, what is the function of such structures? What is the genetic origin of self superantigens? And is self superantigen an appropriate designation for these structures? The M/s loci were originally identified by Festenstein (1973) by mixing lymphocytes of different mouse strains in culture, an in vitro correlate of graft rejection. When two donor strains differ at M/s, the T cells of one strain recognize this difference and are activated to proliferate. Of in-
terest initially was the fact that this locus is unlinked to the major histocompatibility complex (MHC), the cluster of genes on chromosome 17 that controls rapid graft rejection (differences at MHC also induce strong T cell proliferation in mixed lymphocyte culture). The MHC owes its effects on tissue grafting to its remarkable polymorphism and its role in presenting antigens to the T lymphocytes which control all immune responses. T lymphocytes do not recognize foreign antigens directly, but as a molecular complex of a small peptide fragment of the antigen (40-20 amino acids) held in the highly polymorphic peptide binding site of an MHC molecule. Because the ligand recognized by T cells consists of this complex, a T cell can only recognize a given peptide when it is bound by a particular MHC molecule. This latter property is known as MHC restriction. This complex recognition event is mediated by the TCR, a structure highly homologous to the Fab fragment of an antibody molecule (and thus presumed to fold in a similar pattern). The variable (V) regions of the TCR are assembled from five gene segments, Va and Ja, which assemble the a chain V region, and Va Dp, and JB, which assemble the p chain V region. Furthermore, at each site of gene segment joining, nucleotides are removed and added during the recombination event, generating tremendous diversity in receptor structure. Careful analysis of antigen recognition has shown that all these gene segments acting together determine the antigen specificity and MHC restriction of the TCR (see figure, left). It has not yet been possible to segregate MHC recognition from antigen recognition in the TCR. Rather, the outer end of the variable region appears to form a complex surface that interacts with the complex peptide-MHC ligand, much as an antibody molecule binds its protein antigen (Amit et al., 1986). A second feature that makes the M/s locus remarkable is that it could stimulate such a large percentage of T cells. Although this could suggest that M/s is a mitogen that acts on a separate receptor on the T cell, several facts argue compellingly for a different interpretation. As shown in the table, the T cell response to M/s involves class II MHC molecules (which present conventional protein antigens to
Models of the Interaction of the T Cell Receptor with Its Ligands.
Llgand
(Left) The recognition of the complex peptide-class II MHC ligand by the TCR and its CD4 coreceptor is shown with all the genetic elements of the TCR involved in peptide-MHC recognition. (Center) The current consensus model (Janeway et al., 1989b; Marrack and Kappler, 1990) of responses to staphylococcal enterotoxins
and M/s shows binding of the superantigento the outer faces of class II MHC and the Vp region of the TCR near amino acid residues 22, 70. and 71 (Pullen 81 al., 1990); peptide binding to MHC IS irrelevant in responses to superantigens (Dellabona e1 al., 1989). (Right) The coligand model of antigen recognition with the coligand binding less avidly to Vp and potentiating the interaction of the TCR with its specific peptide-class II MHC ligand, allowing lower levels of peptide to elicit a response (Janeway et al., 1983, 1989a).
Cell 660
Properties
of T Cell Responses
to Superantigens
Property
Proteins
M/s-l
Staphylococcal Enterotoxins
Frequency of responding T cells MHC restriction of response Critical regions of the TCR Direct binding to MHC class II Processing required for response Inhibition by anti-class II MHC Inhibition by anti-CD4
~11105
-115
WV115
Yes
No
For details, see Janeway
V~J~&DBJ,T‘4
No
VP
No
?
Yes
Yes
?
No
Yes
Yes
Yes
Yes
Yes
Yes
et al., 1969b.
CD4+ T cells), the CD4 molecule involved in class II MHC recognition, and the TCR itself. However, the role of class II MHC molecules is clearly distinct in responses to M/s, because most class II MHC molecules can present M/s to a single clone of T cells; this lack of MHC restriction is never seen in T cell responses to conventional protein antigens. What has stimulated intense recent interest in M/s is the finding that responsiveness to M/s depends only on the part of the TCR encoded by the Vp gene segment; the other gene segments that encode the TCR play little role in this process (Kappler et al., 1988; MacDonald et al., 1988). Because a given M/s allele can stimulate T cells expressing receptors encoded by several of the 20 different V8 gene segments, a high fraction of T cells respond to differences at M/s. Furthermore, mice that express stimulatory alleles at M/s eliminate those T cells expressing the responsive TCR from the peripheral T cell pool; this elimination, which occurs by clonal deletion within the thy mus during T cell maturation, guarantees self tolerance. How does M/s achieve its effects? A strong clue comes from studies of a second set of superantigens, the enterotoxins produced by staphylococci (Janeway et al., 1988; White et al., 1989; reviewed in Marrack and Kappler, 1990). The staphylococcal enterotoxins have T cell-stimulating properties that are very similar to those of M/s (see table). However, they have the advantage that they are of known structure and are available as highly purified proteins. The staphylococcal enterotoxins bind directly to class II MHC molecules without antigen processing (the proteolytic degradation required for T cell recognition of conventional antigens). Staph. enterotoxins appear to have two distinct binding functions, one’to’ class II MHC and the other to the VP region of the TCR, as shown in the consensus model for the action of M/s and staphylococcal enterotoxins in stimulating T cell responses (see figure, center). The binding of staphylococcal enterotoxins and MIS to both class II MHC and Vp allows TCR cross-linking in conjunction with CD4 coreceptor molecules, thus strongly activating the T cell. This response occurs regardless of the peptide bound to the MHC molecule. This model has recently received strong support from studies of site-
directed mutants of the two relevant target structures, class II MHC and VP Dellabona et al. (1989) have shown that mutations to the class II MHC peptide binding site disrupt peptide, but not staphylococcal enterotoxin, presentation to cloned T cell lines; thus, staphylococcal enterotoxins bind to a site distinct from the peptide binding cleft on MHC molecules. Second, Pullen et al. (1990) have recently mapped the sites on the TCR involved in M/s recognition to the lateral face of the V8 region, well away from the hypervariable loops that determine antigen recognition and MHC restriction. Why do M/s and staphylococcal enterotoxins adopt similar strategies in T cell activation? It has been argued that staphylococcal enterotoxins are important virulence factors-one effect of injecting staphylococcal enterotoxins into mice is to suppress the ability to mount an immune response; M/s also shares this capability. Furthermore, staphylococcal enterotoxins cause at least some of their pathological effects, such as abrupt weight loss, by their action on T cells in vivo, perhaps by inducing the secretion of inflammatory cytokines such as tumor necrosis factors and interferon--r. In view of this, Marrack and Kappler (1990) have proposed that the mouse was forced to develop structures analogous to the toxins in order to protect the host from this bacterial threat by deleting the responding T cells during intrathymic development. This proposal is based on the finding that several such structures exist, each mapping to distinct sites in the genome and causing the deletion of T cells expressing virtually all receptors encoded by distinct subsets of one or more VP gene segments. Furthermore, by breeding mice in which T cells expressing the relevant VpS were deleted, resistance to the pathological effects of staphylococcal enterotoxins could be obtained (Marrack et al., 1990). An alternative point of view is that M/s has a distinct function in the mouse independent of T cell deletion, and it is this hypothesis that is supported by the data of Cazenave et al. (1990). They found that wild mice have subtle changes in either M/s-like loci or the Vf3 gene segments whose products they bind, such that T cells expressing these VP genes are not deleted. These results suggest that Vp deletion may not be the main biological role of M/s-like structures. If this interpretation is correct, it raises a critical question: what is the true biological function of self superantigens? There are three major stages of T cell development at which TCR-MHC ligand interactions are known to play a role: positive selection of developing thymocytes to respond to self MHC molecules, clonal deletion of potentially autoreactive T cells, and antigen recognition during the induction or effector phases of a T cell response. At each of these stages, TCR-MHC interactions are influenced by M/s polymorphism. Clonal deletion by M/s has already been discussed. A role of M/s-like structures in the positive selection of the TCR repertoire in the thymus has also been observed (Benoist and Mathis, 1989). Finally, it has been shown that polymorphism at M/s can potentiate antigen presentation by at least an order of magnitude (Janeway et al., 1983). This suggests that M/S products and related proteins might play a role in all interactions be-
Minireview 661
tween TCR and class II MHC molecules, perhaps by stabilizing or orienting the TCR’s interaction with its MHC ligand. We have termed this the coligand function of M/S and have proposed the term coligand to describe this general class of molecules (Janeway et al., 1989a). The coligand hypothesis states that all TCR-MHC interactions are stabilized by a coligand, a member of a family of related molecules. Coligand proteins potentiate T cell responses to limiting antigen doses, allowing responses to occur more rapidly while retaining strict antigen specificity; peptide recognition by the TCR is critical in these events (see figure, right). This hypothesis raises two further questions: what is the meaning of polymorphism in M/s, and why have similar structures not been detected in humans? The answer to the first question would be that point mutations in either Vp or the coligand could upset a very delicate balance of binding, with increased binding of the coligand to Vp leading to direct T cell stimulation and its counterpart, clonal deletion. The subtlety of these effects is readily observable in the studies of Pullen et al. (1990) in which single amino acid changes in V8 can lead to a response, and Cazenave et al. (1990) in which a change of two amino acids in VP led to loss of a response. The delicate balance between response and nonresponse suggests that coligands have evolved to facilitate the response of T cells to antigen, increasing the T cell’s sensitivity to antigen to a point at which a very low level of foreign antigen will still elicit a potent and specific response. This same process may also affect responses to self peptides in autoimmunity, accounting for the striking preponderance of a single Vf3 among T cells involved in a variety of diseases (Heber-Katz and Acha-Orbea, 1989). The question of similar effects in humans currently lacks an answer, and must probably wait until the genes encoding one or more human coligands have been cloned. Finally, if the coligand hypothesis is correct, what is the likely genetic origin of these structures? Which came first: the coligands or the bacterial toxins? It seems possible that a coligand gene was acquired from host DNA by bacteria, and this gene mutated to give rise to the toxins, retaining its dual MHC and V8 binding capacity through selection for virulence. The effects of the toxins may have led, in turn, to the selection of polymorphic variants of host coligands able to delete T cells bearing potentially responsive V8 gene segments. Certainly, if coligands and toxins turn out to be homologs rather than analogs, then divergent rather than convergent evolution must be operative. It is not unheard of for pathogens to acquire genes from their hosts and use them in virulence. Oncogenes are the most familiar example; but in addition, Epstein-Barr virus has acquired the gene for IL-lo, which may contribute to the ability of this virus to stably infect B cells via inhibition of interferon7 secretion by protective host T cells (Moore et al., 1990). Furthermore, the gene responsible for virulence of Yersinia, the bacteria that causes plague, encodes a functional protein-tyrosine phosphatase; because bacteria contain no tyrosine phosphate, whether this gene is of bacterial origin is questionable (Guan and Dixon, 1990). Finally, the E. coli gene pa@ may have derived
from the mammalian gene for CD5 or a related structure (Holmgren and Branden, 1989). Host cell DNA may be a valuable source of genetic raw material for the development of virulence factors. In this regard, it will be interesting to determine the evolutionary relationships between coligands and bacterial toxins. If the coligand hypothesis is correct, I believe the term self superantigen can be safely replaced. References Amit, A. G., Mariuzza, R. A., Phillips, S. E. V., and Poljak. Ft. J. (1986). Science 233, 747-753. Benoist, C., and Mathis. D. (1969). Cell 58, 1027-1033
Cazenave,P-A.,
Marche, P N., Jouvin-Marche, E., Voegtle, D., Bonhomme, F., Bandeira, A., and Coutinho, A. (1990). Cell 63, this issue. Dellabona, P, Peccoud, J., Benoist, C., and Mathis, D. (1969). Cold Spring Harbor Symp. Quant. Biol. 54, 375-381. Festenstein,
H. (1973). Transplant. Rev. 75, 29-56.
Guan, K., and Dixon, J. E. (1990). Science 249, 553-556. Heber-Katz, 164-169. Holmgren,
E., and Acha-Orbea,
H. (1969). Immunol.
Today 10,
A., and Branden, C.-l. (1989). Nature 34.2, 248-251.
Janeway, C. A., Jr., Conrad, I? J., Tite, J., Jones, B., and Murphy, D. 8. (1983). Nature 306, 80-82. Janeway, C. A., Jr., Chalupny, J., Conrad, P J., and Buxser, S. (1968). J. Immunogenet. 15, 161-169. Janeway, C. A., Jr., Dianzani, U., Portoles, P., Rath, S., Reich, E.-P, Rojo, J., Yagi, J., and Murphy, D. B. (1989a). Cold Spring Harbor Symp. Quant. Biol. 54, 657-666. Janeway, C. A., Jr., Yagi, J., Conrad, I? J., Katz, M. E., Jones, B., Vroegrop, S., and Buxser, S. (1989b). Immunol. Rev. 707 61-88. Kappter, J. W., Staerz, U., White, J., and Marrack, P C. (1988). Nature 332, 35-40. Kappler, J. W., Pullen, A., Callahan, J., Char, Y., Herman, A., White, J., Potts, W., Wakeland, E., and Marrack. P (1989). Cold Spring Harbor Symp. Quant. Biol. 54, 401-406. MacDonald, H. R., Schneider, R., Lees, R. K., Howe, R. C., AchaOrbea, H., Festenstein, H., Zinkernagel, R. M., and Hengartner, H. (1988). Nature 332, 40-45. Marrack, P, and Kappler, J. (1990). Science 248, 705-711. Marrack, P, Blackman, M., Kushnir, E., and Kappler, J. W. (1990). J. Exp. Med. 777, 455-464. Moore, K. W., Vieira, P, Fiorentino, D. F., Trounstine, M. L., Khan, T A., and Mosmann, T. R. (1990). Science 248, 1230-1234. Putten, A. M., Wade, T., Marrack, P., and Kappler, J. W. (1990). Cell 87, 1365-1374. White, J., Herman, A., Pullen, A. M., Kubo, R., Kappler, J. W., and Marrack, P (1989). Cell 56, 27-35.
M inireview
Self Superantigens?
Charles A. Janeway, Jr. Section of lmmunobiology Yale University School of Medicine Howard Hughes Medical institute New Haven, Connecticut 06510
The term superantigen has been proposed by White et al. (1989) to describe several structures that stimulate T lymphocytes by a novel mechanism. Superantigens are distinguished from conventional antigens by the high frequency of responding T cells (-50/o-25%); they are also distinguished from polyclonal T cell mitogens, such as concanavalin A, by the fact that the stimulus activates the T cell by binding a specific site in the variable portion of the I3 chain of the specific T cell antigen receptor (TCR). At present, there are two main categories of superantigens with closely similar properties: the toxic molecules produced by certain bacteria and the still-uncharacterized products of several unlinked genetic loci in the mouse, the best known of which are called M/s (minor lymphocyte stimulating). Mice that express certain self superantigens eliminate those T cells whose TCR p chain would confer reactivity to the self superantigens (Kappler et al., 1988; MacDonald et al., 1988). Kappler and Marrack have shown that it is the T cell response to bacterial toxins that actually causes pathology and have speculated that the mouse developed self superantigens to eliminate these T cells through clonal deletion (Kappler et al., 1989). However, Cazenave et al. (1990) present data that they use to argue against this hypothesis of convergent evolution. This raises several interesting questions: How do superantigens activate T cells? If M/s did not evolve to delete toxin-responsive T cells, what is the function of such structures? What is the genetic origin of self superantigens? And is self superantigen an appropriate designation for these structures? The M/s loci were originally identified by Festenstein (1973) by mixing lymphocytes of different mouse strains in culture, an in vitro correlate of graft rejection. When two donor strains differ at M/s, the T cells of one strain recognize this difference and are activated to proliferate. Of in-
terest initially was the fact that this locus is unlinked to the major histocompatibility complex (MHC), the cluster of genes on chromosome 17 that controls rapid graft rejection (differences at MHC also induce strong T cell proliferation in mixed lymphocyte culture). The MHC owes its effects on tissue grafting to its remarkable polymorphism and its role in presenting antigens to the T lymphocytes which control all immune responses. T lymphocytes do not recognize foreign antigens directly, but as a molecular complex of a small peptide fragment of the antigen (40-20 amino acids) held in the highly polymorphic peptide binding site of an MHC molecule. Because the ligand recognized by T cells consists of this complex, a T cell can only recognize a given peptide when it is bound by a particular MHC molecule. This latter property is known as MHC restriction. This complex recognition event is mediated by the TCR, a structure highly homologous to the Fab fragment of an antibody molecule (and thus presumed to fold in a similar pattern). The variable (V) regions of the TCR are assembled from five gene segments, Va and Ja, which assemble the a chain V region, and Va Dp, and JB, which assemble the p chain V region. Furthermore, at each site of gene segment joining, nucleotides are removed and added during the recombination event, generating tremendous diversity in receptor structure. Careful analysis of antigen recognition has shown that all these gene segments acting together determine the antigen specificity and MHC restriction of the TCR (see figure, left). It has not yet been possible to segregate MHC recognition from antigen recognition in the TCR. Rather, the outer end of the variable region appears to form a complex surface that interacts with the complex peptide-MHC ligand, much as an antibody molecule binds its protein antigen (Amit et al., 1986). A second feature that makes the M/s locus remarkable is that it could stimulate such a large percentage of T cells. Although this could suggest that M/s is a mitogen that acts on a separate receptor on the T cell, several facts argue compellingly for a different interpretation. As shown in the table, the T cell response to M/s involves class II MHC molecules (which present conventional protein antigens to
Models of the Interaction of the T Cell Receptor with Its Ligands.
Llgand
(Left) The recognition of the complex peptide-class II MHC ligand by the TCR and its CD4 coreceptor is shown with all the genetic elements of the TCR involved in peptide-MHC recognition. (Center) The current consensus model (Janeway et al., 1989b; Marrack and Kappler, 1990) of responses to staphylococcal enterotoxins
and M/s shows binding of the superantigento the outer faces of class II MHC and the Vp region of the TCR near amino acid residues 22, 70. and 71 (Pullen 81 al., 1990); peptide binding to MHC IS irrelevant in responses to superantigens (Dellabona e1 al., 1989). (Right) The coligand model of antigen recognition with the coligand binding less avidly to Vp and potentiating the interaction of the TCR with its specific peptide-class II MHC ligand, allowing lower levels of peptide to elicit a response (Janeway et al., 1983, 1989a).
Cell 660
Properties
of T Cell Responses
to Superantigens
Property
Proteins
M/s-l
Staphylococcal Enterotoxins
Frequency of responding T cells MHC restriction of response Critical regions of the TCR Direct binding to MHC class II Processing required for response Inhibition by anti-class II MHC Inhibition by anti-CD4
~11105
-115
WV115
Yes
No
For details, see Janeway
V~J~&DBJ,T‘4
No
VP
No
?
Yes
Yes
?
No
Yes
Yes
Yes
Yes
Yes
Yes
et al., 1969b.
CD4+ T cells), the CD4 molecule involved in class II MHC recognition, and the TCR itself. However, the role of class II MHC molecules is clearly distinct in responses to M/s, because most class II MHC molecules can present M/s to a single clone of T cells; this lack of MHC restriction is never seen in T cell responses to conventional protein antigens. What has stimulated intense recent interest in M/s is the finding that responsiveness to M/s depends only on the part of the TCR encoded by the Vp gene segment; the other gene segments that encode the TCR play little role in this process (Kappler et al., 1988; MacDonald et al., 1988). Because a given M/s allele can stimulate T cells expressing receptors encoded by several of the 20 different V8 gene segments, a high fraction of T cells respond to differences at M/s. Furthermore, mice that express stimulatory alleles at M/s eliminate those T cells expressing the responsive TCR from the peripheral T cell pool; this elimination, which occurs by clonal deletion within the thy mus during T cell maturation, guarantees self tolerance. How does M/s achieve its effects? A strong clue comes from studies of a second set of superantigens, the enterotoxins produced by staphylococci (Janeway et al., 1988; White et al., 1989; reviewed in Marrack and Kappler, 1990). The staphylococcal enterotoxins have T cell-stimulating properties that are very similar to those of M/s (see table). However, they have the advantage that they are of known structure and are available as highly purified proteins. The staphylococcal enterotoxins bind directly to class II MHC molecules without antigen processing (the proteolytic degradation required for T cell recognition of conventional antigens). Staph. enterotoxins appear to have two distinct binding functions, one’to’ class II MHC and the other to the VP region of the TCR, as shown in the consensus model for the action of M/s and staphylococcal enterotoxins in stimulating T cell responses (see figure, center). The binding of staphylococcal enterotoxins and MIS to both class II MHC and Vp allows TCR cross-linking in conjunction with CD4 coreceptor molecules, thus strongly activating the T cell. This response occurs regardless of the peptide bound to the MHC molecule. This model has recently received strong support from studies of site-
directed mutants of the two relevant target structures, class II MHC and VP Dellabona et al. (1989) have shown that mutations to the class II MHC peptide binding site disrupt peptide, but not staphylococcal enterotoxin, presentation to cloned T cell lines; thus, staphylococcal enterotoxins bind to a site distinct from the peptide binding cleft on MHC molecules. Second, Pullen et al. (1990) have recently mapped the sites on the TCR involved in M/s recognition to the lateral face of the V8 region, well away from the hypervariable loops that determine antigen recognition and MHC restriction. Why do M/s and staphylococcal enterotoxins adopt similar strategies in T cell activation? It has been argued that staphylococcal enterotoxins are important virulence factors-one effect of injecting staphylococcal enterotoxins into mice is to suppress the ability to mount an immune response; M/s also shares this capability. Furthermore, staphylococcal enterotoxins cause at least some of their pathological effects, such as abrupt weight loss, by their action on T cells in vivo, perhaps by inducing the secretion of inflammatory cytokines such as tumor necrosis factors and interferon--r. In view of this, Marrack and Kappler (1990) have proposed that the mouse was forced to develop structures analogous to the toxins in order to protect the host from this bacterial threat by deleting the responding T cells during intrathymic development. This proposal is based on the finding that several such structures exist, each mapping to distinct sites in the genome and causing the deletion of T cells expressing virtually all receptors encoded by distinct subsets of one or more VP gene segments. Furthermore, by breeding mice in which T cells expressing the relevant VpS were deleted, resistance to the pathological effects of staphylococcal enterotoxins could be obtained (Marrack et al., 1990). An alternative point of view is that M/s has a distinct function in the mouse independent of T cell deletion, and it is this hypothesis that is supported by the data of Cazenave et al. (1990). They found that wild mice have subtle changes in either M/s-like loci or the Vf3 gene segments whose products they bind, such that T cells expressing these VP genes are not deleted. These results suggest that Vp deletion may not be the main biological role of M/s-like structures. If this interpretation is correct, it raises a critical question: what is the true biological function of self superantigens? There are three major stages of T cell development at which TCR-MHC ligand interactions are known to play a role: positive selection of developing thymocytes to respond to self MHC molecules, clonal deletion of potentially autoreactive T cells, and antigen recognition during the induction or effector phases of a T cell response. At each of these stages, TCR-MHC interactions are influenced by M/s polymorphism. Clonal deletion by M/s has already been discussed. A role of M/s-like structures in the positive selection of the TCR repertoire in the thymus has also been observed (Benoist and Mathis, 1989). Finally, it has been shown that polymorphism at M/s can potentiate antigen presentation by at least an order of magnitude (Janeway et al., 1983). This suggests that M/S products and related proteins might play a role in all interactions be-
Minireview 661
tween TCR and class II MHC molecules, perhaps by stabilizing or orienting the TCR’s interaction with its MHC ligand. We have termed this the coligand function of M/S and have proposed the term coligand to describe this general class of molecules (Janeway et al., 1989a). The coligand hypothesis states that all TCR-MHC interactions are stabilized by a coligand, a member of a family of related molecules. Coligand proteins potentiate T cell responses to limiting antigen doses, allowing responses to occur more rapidly while retaining strict antigen specificity; peptide recognition by the TCR is critical in these events (see figure, right). This hypothesis raises two further questions: what is the meaning of polymorphism in M/s, and why have similar structures not been detected in humans? The answer to the first question would be that point mutations in either Vp or the coligand could upset a very delicate balance of binding, with increased binding of the coligand to Vp leading to direct T cell stimulation and its counterpart, clonal deletion. The subtlety of these effects is readily observable in the studies of Pullen et al. (1990) in which single amino acid changes in V8 can lead to a response, and Cazenave et al. (1990) in which a change of two amino acids in VP led to loss of a response. The delicate balance between response and nonresponse suggests that coligands have evolved to facilitate the response of T cells to antigen, increasing the T cell’s sensitivity to antigen to a point at which a very low level of foreign antigen will still elicit a potent and specific response. This same process may also affect responses to self peptides in autoimmunity, accounting for the striking preponderance of a single Vf3 among T cells involved in a variety of diseases (Heber-Katz and Acha-Orbea, 1989). The question of similar effects in humans currently lacks an answer, and must probably wait until the genes encoding one or more human coligands have been cloned. Finally, if the coligand hypothesis is correct, what is the likely genetic origin of these structures? Which came first: the coligands or the bacterial toxins? It seems possible that a coligand gene was acquired from host DNA by bacteria, and this gene mutated to give rise to the toxins, retaining its dual MHC and V8 binding capacity through selection for virulence. The effects of the toxins may have led, in turn, to the selection of polymorphic variants of host coligands able to delete T cells bearing potentially responsive V8 gene segments. Certainly, if coligands and toxins turn out to be homologs rather than analogs, then divergent rather than convergent evolution must be operative. It is not unheard of for pathogens to acquire genes from their hosts and use them in virulence. Oncogenes are the most familiar example; but in addition, Epstein-Barr virus has acquired the gene for IL-lo, which may contribute to the ability of this virus to stably infect B cells via inhibition of interferon7 secretion by protective host T cells (Moore et al., 1990). Furthermore, the gene responsible for virulence of Yersinia, the bacteria that causes plague, encodes a functional protein-tyrosine phosphatase; because bacteria contain no tyrosine phosphate, whether this gene is of bacterial origin is questionable (Guan and Dixon, 1990). Finally, the E. coli gene pa@ may have derived
from the mammalian gene for CD5 or a related structure (Holmgren and Branden, 1989). Host cell DNA may be a valuable source of genetic raw material for the development of virulence factors. In this regard, it will be interesting to determine the evolutionary relationships between coligands and bacterial toxins. If the coligand hypothesis is correct, I believe the term self superantigen can be safely replaced. References Amit, A. G., Mariuzza, R. A., Phillips, S. E. V., and Poljak. Ft. J. (1986). Science 233, 747-753. Benoist, C., and Mathis. D. (1969). Cell 58, 1027-1033
Cazenave,P-A.,
Marche, P N., Jouvin-Marche, E., Voegtle, D., Bonhomme, F., Bandeira, A., and Coutinho, A. (1990). Cell 63, this issue. Dellabona, P, Peccoud, J., Benoist, C., and Mathis, D. (1969). Cold Spring Harbor Symp. Quant. Biol. 54, 375-381. Festenstein,
H. (1973). Transplant. Rev. 75, 29-56.
Guan, K., and Dixon, J. E. (1990). Science 249, 553-556. Heber-Katz, 164-169. Holmgren,
E., and Acha-Orbea,
H. (1969). Immunol.
Today 10,
A., and Branden, C.-l. (1989). Nature 34.2, 248-251.
Janeway, C. A., Jr., Conrad, I? J., Tite, J., Jones, B., and Murphy, D. 8. (1983). Nature 306, 80-82. Janeway, C. A., Jr., Chalupny, J., Conrad, P J., and Buxser, S. (1968). J. Immunogenet. 15, 161-169. Janeway, C. A., Jr., Dianzani, U., Portoles, P., Rath, S., Reich, E.-P, Rojo, J., Yagi, J., and Murphy, D. B. (1989a). Cold Spring Harbor Symp. Quant. Biol. 54, 657-666. Janeway, C. A., Jr., Yagi, J., Conrad, I? J., Katz, M. E., Jones, B., Vroegrop, S., and Buxser, S. (1989b). Immunol. Rev. 707 61-88. Kappter, J. W., Staerz, U., White, J., and Marrack, P C. (1988). Nature 332, 35-40. Kappler, J. W., Pullen, A., Callahan, J., Char, Y., Herman, A., White, J., Potts, W., Wakeland, E., and Marrack. P (1989). Cold Spring Harbor Symp. Quant. Biol. 54, 401-406. MacDonald, H. R., Schneider, R., Lees, R. K., Howe, R. C., AchaOrbea, H., Festenstein, H., Zinkernagel, R. M., and Hengartner, H. (1988). Nature 332, 40-45. Marrack, P, and Kappler, J. (1990). Science 248, 705-711. Marrack, P, Blackman, M., Kushnir, E., and Kappler, J. W. (1990). J. Exp. Med. 777, 455-464. Moore, K. W., Vieira, P, Fiorentino, D. F., Trounstine, M. L., Khan, T A., and Mosmann, T. R. (1990). Science 248, 1230-1234. Putten, A. M., Wade, T., Marrack, P., and Kappler, J. W. (1990). Cell 87, 1365-1374. White, J., Herman, A., Pullen, A. M., Kubo, R., Kappler, J. W., and Marrack, P (1989). Cell 56, 27-35.