Superantigens: mechanism of T-cell stimulation and role in immune responses.

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Annu. Rev. Immunol. 1991.9:745-72 Copyright © 1991 by Annual Reviews Inc. All rights reserved

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SUPERANTIGENS: Mechanism of T -Cell Stimulation and Role in Annu. Rev. Immunol. 1991.9:745-772. Downloaded from www.annualreviews.org by University of Nebraska - Lincoln on 09/16/13. For personal use only.

Immune Responses Andrew Herman, John W. Kappler,1 Philippa Marrack,I,2 and Ann M. Pullen Howard Hughes M edical Institute, Department of Medicine, National Jewish Center for Immunology and Respiratory Medicine, 1 400 Jackson Street, Denver, Colorado 80206 Departments of I Microbiology and Immunology and Medicine, 2 Biochemistry, Biophysics and Genetics, University of Colorado Health Sciences Center, Denver, Colorado 80206 KEY WORDS:

T cell receptor, V�

MHC

class

II,

staphylococcal enterotoxins,

Mis,

element

Abstract Superantigens combine with MHC class-II molecules to form the ligands that stimulate T cells via the Vp element of the T-cell receptor. Two groups of superantigens have been described so far: first, endogenous murine products that include the Mis determinants, and second, bacterial products such as the Staphylococcal enterotoxins. Here, we review studies that address the interactions between the foreign superantigens and MHC class-II molecules, the mechanism ofT-cell stimu lation, and the role that tolerance to self-superantigens plays in shaping the T-cell repertoire. We speculate on the possible evolutionary significance of superantigens.

INTRODUCTION Minor lymphocyte stimulating (MIs) determinants were first detected, in the early 1970s, by their ability to stimulate a strong primary mixed 745 0732--0582/91/0410-0745$02.00

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HERMAN ET AL

lymphocyte reaction (MLR) between cells from mice of the same major histocompatibility complex (MHC) haplotype

( 1 ).

In these reactions a

large number of naive T cells were responding to MIs determinants pre sented by MHC class-II molecules on the surface of a variety of cell types. Gradually the genetics of the MIs system have been clarified, and recently we have begun to understand the mechanism by which so many T cells respond to these determinants. It has also been known for many years that certain bacterial exotoxins are potent T-cell mitogens

(2-4).

The observation that large numbers of

Annu. Rev. Immunol. 1991.9:745-772. Downloaded from www.annualreviews.org by University of Nebraska - Lincoln on 09/16/13. For personal use only.

T cells are stimulated either by MIs determinants or by the toxins has spurred the investigation of the underlying mechanism of this T-cell acti vation. The mode of stimulation of T cells by these toxins may be similar to that of the MIs determinants. We have suggested that the term "super antigen" be used for both MIs determinants and bacterial toxins, since they both stimulate such a high frequency of T cells (5). T cell receptors (TCR) are composed of five variable elements, Va, la, V{3, D{3, and l{3 (reviewed in

6),

all of which contribute to the specific

interaction of T lymphocytes with conventional peptide antigens presented in the context of MHC molecules

(7-9).

There are potentially millions of

possible combinations of these variable elements, and so the frequency of responding T cells to a given conventional antigen is very low. In the last few years the application of monoclonal antibodies specific for V {3 elements of the TCR has led to the demonstration that superantigens stimulate such large numbers of T cells because they stimulate virtually all T cells bearing particular V{3 elements

(10- 1 2).

In this review we compare and contrast how the endogenous murine superantigens (self-superantigens) and the bacterial toxins (foreign super antigens) complex with class-II molecules to form ligands that sub sequently stimulate T cells. We also discuss the possible functions of superantigens and speculate as to their evolutionary significance.

T-CELL RESPONSES TO MLS DETERMINANTS Early Defin ition of Mis Determinants Generally, the frequency of T cells responsive to a particular foreign antigen, such as a viral or parasite protein, is so low ( 1

: 1 04- 1 : 1 06) as to be

undetectable in a primary MLR. In contrast, two groups of determinants stimulate the strong proliferation of T cells when they are cultured with stimulator cells from genetically dissimilar mice. The products of the MHC stimulate between

1: 10

and

1 : 1 00

T cells in a primary MLR

( 1 3).

The

MIs determinants are capable of stimulating even higher numbers of T cells in some MHC-identical mouse strain combinations

( 1 4--1 6).


SUPERANTIGEN STIMULATION OF T CELLS

747

Festenstein studied the strain distribution of MIs determinants and postulated that four alleles, a, b, c, and d, were expressed at the MIs locus ( 1 7). These alleles were thought to encode polymorphic determinants; the MIs" and Mlsd products were strongly stimulatory, the MlsC product was only weakly stimulatory, and Mlsb was nonstimulatory. Festenstein et al (18) used recombinant inbred mice to map the Mis locus to chromosome I . Other workers have since made formal analyses of the allelic relationships between the genes encoding Mis", Mise, and Mlsd and have shown that there are at least two independently segregating Mis loci. Some inves tigators have assigned MIs status to additional non-MHC determinants because they stimulate a primary M LR. These determinants include Mlsx expressed by PLjJ ( 1 9), MIse expressed by C3HjTif (20), and a widely expressed determinant Mlsf that is absent from C58/J (21). The genetics of the MIs system has aroused much controversy. Although several investigators have independently observed similar stimulation pat terns using the MLR, the use of differing cell culture conditions by different researchers may have resulted in some disparities. For example, the weakly stimulatory MlsC described by Festenstein (17) was not always detected by others, while Click and coworkers reported that Mise stimulated almost as well as Mis" in some mouse strain combinations (22). The availability of T-cell clones that responded to MIs" or Mlsc led to a more definitive analysis and clarification of the allelism and polymorphism of the Mis system (23-28). Abe and coworkers (29) demonstrated that the Mlsd phenotype results from expression of both MIs' and MIsC. This mapping has done much to clarify the genetics of the MIs determinants and has been extensively reviewed (30).

New Definition of Mis Determinants The availability of monoclonal antibodies specific for V[3 elements facili tated advances in the study of Mis and led to the new definition of Mis determinants. T cells bearing particular V[3 elements respond to Mis stimu lation, and moreover, T cells bearing these reactive V[3s are eliminated during development in the thymus of mice expressing particular Mis deter minants. Consequently, we favor the definition of the Mis determinants, and of other self-superantigens, by their V[3 specificity. The interaction between the self-superantigens and TCR V[3 elements are discussed in more detail below. This new definition of Mis determinants and the accumulation of a wealth of data on their properties has led to an attempt to simplify the nomenclature of the MIs system. It has been proposed that each MIs locus be numbered, and that the stimulatory allele at each locus be designated a, while the null or nonstimulatory allele be designated b (28). Table 1

748

HERMAN ET AL Table 1

MIs loci expressed by prototypic strains Festenstein's MIs designation

AKR B IO.Br

a b c

,a, 2b, 3b ,b, 2b, 3b Ib, 2a, 3a

CBA/l

d

1",

e3H


Newly proposed Mis designation

Strain

either 2a or 3a

shows a comparison of this new nomenclature with that of the original nomenclature of Festenstein for some prototypic strains. For simplicity, we use the new nomenclature in this review.

Role of Class

II

Early experiments suggested that MHC class-II molecules were necessary for T-cell responses to MIs (31) and that anti--class II, but not anti--class I, antibodies were shown to block MIs-responses (32-34). Subsequently, studies using T-cell clones and hybridomas showed that presenting cells from most, but not all, MHC haplotypes could present MIs determinants to T cells, regardless of the MHC type of the T-cell itself (35). There is a hierarchy for MHC class-II presentation of MIs; namely H-2k , H-2d> H-2b> H-2q (10, 12). The promiscuity of MHC presentation of Mis and other self-superantigens is in marked contrast to the presentation of conventional antigens. Only MHC haplotype-matched accessory cells can present pep tide fragments of conventional antigens to a particular T cell (36-39).

Tissue Distribution of Mis The question of whether or not a particular cell type expresses MIs is complicated by the fact that stimulation of T cells by MIs determinants requires the association of MIs gene products with M HC class-II molecules on the presenting cells. All investigators agree that B cells can present MIs antigens (40), but there is still controversy over whether macrophages and dendritic cells express and present MIs determinants. Several reports indicate that macrophages (32, 41) and dendritic cells (42) can present MIs determinants; however, Webb and coworkers (43) were unable to confirm these findings using macrophages and dendritic cell populations thor oughly depleted of B cells. Hamilos et al (42) have demonstrated that dendritic cells are weak stimulators of Mis-specific T-cell hybridomas but are very potent stimulators of a primary MLR. These data are consistent with the findings of Steinman and coworkers (44, 45), who have shown that dendritic cells are potent stimulators of primary T-cell activation to alloantigens and protein antigens, and they may help to explain the

749



discrepancies between the results from different investigators. Recently T cell blasts have been shown to express MIs (46); Webb & Sprent (47) have injected neonatal mice with different cell types to show that CD8+ T cells are the most potent cell type for induction of MIs-induced tolerance. This controversy over which cell types present Mis may also be explained by the demonstration that MIs can be transferred from one cell to another in vitro (35) and in vivo (12). These experiments showed the transfer of Mis determinants from cells bearing a nonpermissive haplotype (H-2q) to a haplotype capable of presentation (H-2k), to facilitate the stimulation or deletion of Mis-reactive T cells.

T-CELL RESPONSES TO FOREIGN SUPERANTIGENS Numerous studies on Mis determinants have provided a clearer picture of the genetics of this self-superantigen system. Yet despite many attempts to define the nature of self-superantigens, this characterization has thus far remained elusive. In contrast, several bacterial exotoxins, known for many years to be extremely potent inducers of lymphocyte mitogenesis, have been isolated and sequenced. As they share several important properties with self-superantigens, we have termed these toxins foreign superantigens.

Foreign Superantigens Are Associated with Bacterial Diseases A number of exotoxins are secreted by certain Gram positive bacteria, including Staphylococcus aureus and Streptococcus pyogenes, and by Mycoplasma arthritidis. These proteins have been implicated as the causa tive agents in a number of diseases (see Table 2). Staphylococcal entero toxins (SE) cause almost a quarter of food poisoning cases in the United Table

2

Diseases caused by foreign superantigens Superantigens

Staphylococcal enterotoxins (SEA, B, C I -3, D, E) TSST-I Exfoliating toxins A and B Streptococcal pyrogenic exotoxins (SPE-A, B, C, D) Mycoplasma arthritidis supernatant (MAS)

Disease

References

Food poisoning Shock Toxic shock syndrome Scalded skin syndrome Shock Rheumatic fever Scarlet fever Arthritis Shock

48,49 50-52 53 54-56

57


750

HERMAN ET AL

States (58). A potentially fatal disorder, toxic shock syndrome, is now known to be caused by the Staphylococcal toxins, TSST- l, SEB, SEC l , o r b y Streptococcal pyrogenic exotoxins (SPE) (59). The Staphylococcal exfoliating toxins (ExF) are the etiologic agents in scalded skin syndrome, an extremely debilitating, shock-like disease (60). A factor found in Myco plasma arthritidis supernatant (MAS) is associated with naturally occur ring arthritis in rodents and causes experimentally induced arthritis in other species (6 1). Moreover, some microorganisms that produce these exotoxins have been linked with autoimmune sequelae; Streptococci that secrete an SPE have been implicated in autoimmune disorders of the heart, kidney, and brain, and in rheumatic fever (56, 62).

Structure of Foreign Superan tigens A number of these exotoxins are small, basic proteins that range in size from 20-30 kilodaItons (kd) (63). Among the best studied are the entero toxins produced by S. aureus. They include a number of structuralIy related enterotoxins that have been termed SEA, B, C l , C2, C3, D, and E. These SEs can be divided into two groups on the basis of their structural homology. SEB is most homologous to SEC ] and SEC3 (64-66). Sequence analyses of SEA, SED, and SEE indicate that these proteins are closely related (67-69) and that SEA and SEE are more than 90% homologous at the amino acid level. Toxic shock syndrome toxin (TSST- l ), the toxin that has been implicated in the majority of toxic shock syndrome cases, is less closely related to the other enterotoxins of S. aureus, and it does not share the conserved disulfide loop found in these SEs (70). The pyrogenic toxins produced by Group A Streptococci comprise a second family of foreign superantigens. These have been implicated in severe, shock-like disorders (54-56). The amino acid sequences of SPE-A, B, C, D (71 , 72) are similar to one another and are somewhat more distantly related to the Staphylococcal enterotoxins. A comprehensive sequence comparison of many of these foreign superantigens can be found in a review by Marrack & Kappler (73). Identification of another foreign superantigen, a protein secreted by M. arthritidis (MAS), has remained more elusive, and MAS has yet to be characterized at the molecular level. The availability of these defined foreign superantigens, in contrast to the absence of any isolated self-superantigens, has enabled workers to address the questions of how these toxins are presented and how they are recognized by T cells.

Foreign Superantigens Bind To MHC Class-II Molecules The Staphylococcal enterotoxins were first named for their association with the symptoms of food poisoning. Whereas the mechanisms by which



75 1

some other bacterial enterotoxins induce emesis had been worked out, and their binding to intestinal cells had been demonstrated, the mode of action of SEs remained enigmatic (58). This problem was resolved by Buxser et al (74) with their demonstration that SEA bound to murine lymphocytes. SEA bound to a single class of receptor, with approximately 3600 sites per cell, with an apparent Kd of 8 x 1 0-7 M. Inhibition studies suggested that SEA, SEB, and SEE bound to the same site (74). Subsequently, experi ments have shown that MHC class-II proteins are the specific receptors for SEs and other foreign superantigens. Several approaches have been used to show that bacterial superantigens interact with MHC class-II molecules. Indirect methods such as the use of anti-MHC monoclonal antibodies to inhibit presentation of toxins (75, 76), and genetic analyses illustrating the necessity for IE expression for T cell stimulation by the M. arthritidis superantigen (77), have indicated that MHC class-II products are involved in foreign superantigen stimulation of lymphocytes. Analyses of mutant cell lines lacking class-II molecules have dem onstrated the absolute requirement for class-II for presentation of foreign superantigens; this has been confirmed by the transfection of MHC class-II genes into class-II negative recipient cell lines. This requirement for MHC class-II products for bacterial superantigen binding and pres entation has been demonstrated for SEA (78), SEB (5, 75), TSST-l (798 1), MAS (77, 82) and the Streptococcal M 5 protein (62). Quantitative binding studies with several of these exotoxins have shown that their affinities for MHC class-II are in the nanomolar range. For ex ample, TSST- l has a Kd of approximately 3 x 1 0- 8 M for human class-II molecules (83), and its affinity for murine I-A molecules is roughly three fold lower (81, 74). The Kd of SEB is 10-30 times higher than that of SEA (84) and TSST- l (85) for human MHC class II. Staphylococcal enterotoxin A (SEA) is the most potent T-cell mitogen known and among the SEs has the highest affinity for class-II molecules.

Presentation of Foreign Superantigens To T Lymphocytes Presentation of self- and foreign superantigens differs from that of con ventional antigens in two important respects: T-lymphocyte stimulation by superantigens appears to circumvent the requirement for strict MHC restriction, and processing of foreign superantigens by the antigen pre senting cell is not required. The ability of a T cell to respond to conventional peptide antigens is dictated by the allele of the polymorphic MHC molecule present on the antigen-presenting cell (36). This central tenet of MHC restriction is vio lated in responses to superantigens. Presentation of superantigens requires


752

HERMAN ET AL

MHC class-II antigens on the presenting cell, but it is much more pro miscuous than that seen with MHC-restricted responses. The MHC allele of the presenting cell does not have to match that of the T cell. Allogeneic as well as autologous MHC molecules can present superantigens to an individual T cell (5, 75). Indeed, xenogeneic MHC class-II molecules will suffice (78, 86-88). This lack of MHC specificity is probably a reflection of the fact that many of the foreign superantigens bind to most class-II antigens. This degeneracy of class-II presentation parallels that seen with T-cell stimulation by the self-superantigens described above. M Is determinants can be presented by most IE alleles and by many IA molecules. Although the MHC allele is not important for superantigen presen tation, several of the SEs show differential binding to class-II isotypes. Most of the SEs appear to bind with higher affinity to murine I-E than to I-A (5, 76). There is a similar hierarchy with human class II, where several SEs bind to HLA-DR (the homologue of IE) > HLA-DQ (the IA analogue) > HLA-DP (86, 89). Toxic shock syndrome toxin 1 and the other SEs differ in their binding to MHC class-II antigens. TSST- l binds to several IA alleles but appar ently does not bind to IE (8 1 , 90). Inhibition studies have shown that the binding site for TSST-l does not overlap with that for SEB (91 ) nor by extension, for SEA and SEE. The fact that TSST- 1 does not show sig nificant binding to human HLA-DP molecules, whereas it has a high affinity for HLA-DR antigens, has been used by Karp et al (92) in experi ments designed to map its binding site on HLA-DR. Using different HLA DR/HLA-DP chimeric molecules, they determined that the a l domain of HLA-DR was important for TSST-I binding. Unlike conventional protein antigens, SEs apparently do not require processing prior to their presentation by MHC class II. Metabolically inactivated presenting cells are still capable of presenting SEs to T cells, in contrast to their inability to present other intact protein molecules to T cells (75, 76, 93). Further evidence that SEs are not presented in the same manner as peptide antigens came from Dellabonna et aI, using a series of mutant I_Ak molecules (94, 95). M utations introduced into the a helical region of the I_Ak a-chain that strongly affected the presentation of a conventional peptide antigen to T cells did not dramatically affect pres entation of SEs. There is, however, a possible exception to this lack of processing for superantigens. There have been conflicting reports as to whether the uncharacterized mitogenic product of Mycoplasma arthritidis, MAS, requires processing for T-cell activation (82, 96). All these data suggest that the polymorphic regions of MHC class-II molecules do not influence stimulation of T cells by foreign superantigens.



753

Some HLA-DR molecules, however, do differ dramatically in their ability to bind and present some SEs (86, 97). Although some T-cell clones and hybridomas reportedly are directly stimulated by SEs in the absence of presenting cells (75, 76), many studies have shown that class-II molecules are essential for foreign superantigen binding and subsequent T-cell activation (5, 62, 75-82). Whereas many workers have demonstrated that SEs bind to MHC class-II molecules, no direct evidence exists for their binding to normal T cells (93). The fact that activated human T cells express HLA-DR and can present SEs may have complicated the interpretation of some experiments suggesting that acces sory cells were not required for the presentation of foreign superantigens to human T cells (98).

SELF-SUPERANTIGEN-Vp INTERACTIONS It has been known for some time that the Mis determinants stimulate a high frequency of responding T cells in the primary MLR ( I ). The availability of monoclonal antibodies specific for TCR V[3 elements facilitated the demonstration that the majority of T cells bearing one, or a few different, V[3 elements respond to stimulation by these poorly understood Mis deter minants ( 1 0-1 2). Mice have about 20 genes encoding V[3 elements (99), so if we assume an equal frequency of expression for each V[3 gene segment this would mean that 5% of T cells would bear a single V[3 and would respond to stimulation by a particular self-superantigen. This provides an explanation for the surprisingly high frequency of responding cells to these determinants in the primary MLR. The anti-V[3 antibodies were also used to demonstrate the clonal elim ination of thymocytes reactive with particular self-superantigenjMHC combinations (100). Subsequent studies on the peripheral T-cell repertoire of mice, both by RNA analysis using Vj3-specific probes and by staining that used anti-Vj3 antibodies, together have shown multiple examples of associations between particular self-superantigens and Vj3 elements. Using the monoclonal antibody KJ23a, Kappler and coworkers (101) showed that T-cell hybridomas bearing V[3 1 7a responded to spleen cells from IE+ mouse strains and that these hybrids were stimulated by a B cell derived superantigen presented by IE molecules ( 1 02). Staining analyses of thymocytes from a variety of mouse strains showed that Vf3 1 7a + cells were absent from the mature medullary population of mice expressing IE, although they were present at significant levels among the immature corti cal thymocytes ( 1 00). This has been interpreted to mean that thymocytes reactive with the B cell-specific superantigen complexed with IE were eliminated during development when they encountered their ligand in the


754

HERMAN ET AL

thymus. This was the first demonstration of tolerance induction by the clonal elimination of self-reactive T cells. Subsequently, the majority of T cells bearing Vf3s 6, 7, 8.1 and 9 were shown to be reactive with Mls- l a (10, 11, lO3- lO5), and Vf33+ T cells to be reactive with Mls-2a and Mls-3a (12, lO6). Pullen et al ( lO7) used both the stimulation of Vf33+ T-cell hybridomas and the lack of peripheral T cells bearing Vf33 to map the Mls-2 and Mls-3 genes to chromosomes 4 and 16, respectively. The availability of monoclonal antibodies specific for various Vf3 elements also allowed the confirmation of earlier results obtained by RNA analysis of T-cell populations, which had suggested that T cells bearing certain Vf3s were absent from the periphery of some mouse strains express ing IE. Palmer and coworkers (108) produced an extensive panel of ran domly generated T-cell hybridomas from MHC-disparate strains, BlO (H_2 b), BlO.BR (H_2 k) and B10.Q (H-2q). They screened RNA from these hybrids by dot blot analysis and showed that T cells bearing V f3s 5, 11, and 12 were represented only at very low frequency among the hybrids from BlO.BR (IE+), whereas these Vf3s were expressed at significant levels in the hybrids from the IE- strains. Antibodies specific for the two mem bers of the Vf35 family ( lO9) and Vf311 (1lO, Il l ) have since been used to confirm the result that T cells bearing these Vf3 elements are eliminated in mice expressing IE. These monoclonal antibodies are being used to facili tate the genetic mapping of the superantigens that complex with IE. Meas uring the levels of Vf35-bearing peripheral T cells of B X D recombinant inbred mice, Woodland et al (109) have shown that C57BLj6 carries a self-superantigen (or co-tolerogen), Etc- I , that maps to chromosome 12. DBAj2 probably also carries a Vf35-deleting self-superantigen that com bines with IE (K. J. GoIlob, D. L. Woodland & E. Palmer, unpublished observations). Vacchio et al (112) have extensively analyzed RNA from peripheral T cells from a number of different strains and have confirmed the above observations on the elimination of T cells reactive with the MIs deter minants and with the self-superantigens complexed with IE. Moreover, they have shown that at least one of the self-superantigens that interacts with IE stimulates both Vf311 and Vf312-bearing T cells, and that T cells bearing Vf316 are also susceptible to elimination by a self-superantigen complexed with IE (113). There have been, however, exceptions to the finding that mice expressing IE have few if any Vf311-bearing T cells. For example, although AjJ and C58jJ mice express IE, they have significant levels of Vf311 + T cells (111). These strains may lack the self-superantigen that complexes with IE and triggers these particular T cells. Ryan et al (21) recently proposed that one


755

of the self-superantigens, when complexed with IE stimulates T cells of C58jJ, be called Mlsf. Over the last few years there have been multiple demonstrations of V {3specific stimulation or deletion of T cells by self-superantigens (see Table 3). Recently, some monoclonal antibody reagents specific for murine Va elements have been generated. However, thus far, analyses of Va expression by T cells from different mouse strains have not indicated any interesting patterns of expression ( 1 1 4).


FOREIGN SUPERANTIGEN-Vp INTERACTIONS The observations that Staphylococcal enterotoxins stimulated large num bers of T lymphocytes, and the apparent clonal variation in SE responses by cloned T cell lines, led to the examination of which variable regions of the TCR play a role in SE responses. The availability of V{3 specific monoclonal antibodies allowed the demonstration that SEs selectively stimulate T cells bearing particular V{3 elements. White et al (5) showed that SEB administration to neonatal mice led to the elimination of virtually all T cells bearing V{33, 8.1, 8.2, and 8.3. In vitro, SEB was also shown to stimulate T cells bearing these V {3s ( 1 1 5). Takimoto and coworkers ( 1 1 6) demonstrated that injection of SEA led to the deletion of V {33- and V/3 1 1 bearing T cells in mice. Similarly, V{3-specific stimulation by SEs has been observed in humans. Kappler et al (117) employed a limited panel of monoclonal antibodies specific for human V{3s to show that the T-cell stimulation by SEs was V{3 dependent. This analysis was expanded by Choi et al ( 1 1 8) using a quantitative polymerase chain reaction and a panel of V{3-specific probes. Table 4 summarizes the foreign superantigens and the TCR V{3 elements with which they interact. It is noteworthy that several murine V{3s that react with self-superantiTable 3

Murine self superantigens

Superantigen

MHC association

V f3 specificity

Mls- I a Mls-2" Mls-3"

IA (not q ) o r IE IA (not q) or IE IA (not q) or IE IE IE IE IE IE

6,7, 8. 1 , 9 3 3 5 7 1 1, 12 16 1 7a

? ? ? ?

References 1 0, I I , 1 03-105 12, 107 1 2, 1 07 1 09 104 1 1 0, 1 11, 1 1 3 1 13 100, 101

756

HERMAN ET AL

Table 4

Vp specificity of foreign superantigens

Superantigen SEA SEE

Murine

References

Human

1 , 3, 1 0, I I , 1 2, 1 7 I I , 1 5, 1 7

liS, 1 1 6

nd

1 15

5 . 1 ,6. 1 -6.3

References

1 17, \ 1 8

8, 18

SED


SEB SECI SEC2 SEC3 TSST- I ExFT MAS

3, 7, (8.2), 8.3 I I, 1 7 (3),7, 8. 1-8.3 ( I I), (\7) 8.2,8.3, 7, I I 8.2, 1 0,

liS

5, 1 2

1 17

5, 76, 1 1 5 1 19 1 15

3, 1 2 , 14, 1 5, 1 7, 20 12

1 17, 1 1 8

1 15

1 1 7, 1 1 8

(3),7, 8.2 15,16, 10, II, 15, 6, 8 . 1 -8 . 3

1 15 1 15 1 15 1 20, 1 2 1

1 2 , 1 3, 14, 1 5, 1 7, 20 5, 1 2 2 2 nd

1 17

117 1 18 118

nd, not determined. The reactivities listed i n parentheses are observed with commercial preparations, but not with recom binant sources of enterotoxins.

gens also respond to SEs. For example, V{J3+ T cells react with Mls-2a and Mls-3", and also respond to several SEs; likewise, VpS.I-bearing cells react with Mls-Ia and a number of SEs. M urine and human Vps have apparently conserved features that lead to similar SE response patterns. T cells bearing human Vp5 and the murine homologue, VP l l , respond to SED and SEE ( 1 17, l IS). TSST- 1 stimulates human T cells expressing VfJ2 and murine T cells bearing the structurally analogous VP1 5 element ( 1 22). The strength of the superantigen-Vp interaction is underscored by thc observation that there is no requirement for accessory molecules on the T cell for foreign superantigen stimulation. T-cell clones and hybridomas lacking CD4 and CD8 usually respond to foreign superantigens (75, 82, 8S). Although in general, recognition of conventional antigens in the context of class II requires CD4, and in the context of class I requires CDS ( 1 23, 1 24), CD8 + T cells can specifically lyse class II-bearing target cells in the presence of very low concentrations of SEs (75, 88, 1 25-1 27). Therefore, it appears that the affinity of the TCR for superantigens is sufficiently high to override the necessity for accessory molecules seen for T-cell recognition of conventional antigen/M HC complexes. Finally, the ability to respond to SEs does not appear to be limited solely to T cells bearing afJ TCR. T cells that display the rxfJ-, CD3 + phenotype reportedly can be stimulated by SEs (75, 82), and Vy9-express ing T cells (128) appear to be responsive to SEA in vitro.


757


SUMMARY OF PROPERTIES OF SUPERANTIGENS The similarities between the MIs-like murine products and the bacterial exotoxins prompted us to propose the term "superantigens" to describe these moieties. Both groups of molecules are presented promiscuously by MHC class-II products and stimulate T cells at high frequency, with the Vp element playing a pivotal role in the response. A summary of these properties of superantigens is presented in Table 5. However, several marked differences exist between the self- and foreign superantigens. The self-superantigens are, as yet, uncharacterized, and they can be detected solely by the response of T cells. Despite many attempts, it has not been possible to generate antisera specific for Mls determinants (30, 129), and repeated attempts to coprecipitate Mis pro ducts with MHC class-II molecules have, to date, proved fruitless (P. Marrack, J. W. Kappler, unpublished observations). In contrast, many of the foreign superantigens are well characterized, and their genes cloned and sequenced (73). The availability of purified bacterial exotoxins has expedited the production of monoclonal antibodies (130; J. W. Kappler, unpublished data). In addition, the binding affinities of the SEs for class II are sufficiently high to allow direct demonstrations ofSE-MHC complexes. Given the lack of structural information for self-superantigens, it is tempting to extend conclusions drawn from studies with bacterial toxins when constructing a model for self-superantigens. However, self- and foreign superantigens show some differences in their ability to stimulate T cells. Only CD4 + T cells respond to MIs determinants in the primary M LR (14), whereas, both CD8 + and CD4 + T cells proliferate in response to the SEs (75). These findings suggest that T-cell stimulation by foreign superantigens results from such a strong interaction that the need for T-cell accessory molecules is bypassed, while formation of the MlsjTCRjMHC complex requires the additional interaction between CD4 and MHC class II for T-cell activation.

Table 5

Properties of superantigens

Property Processing Presentation Frequency of responding murine T cells TCR elements

Conventional antigens

Se\fsuperantigens

Foreign superantigens

Yes M HC-restricted

Most class II

No Most class II

VrxJrxVPDpJp

Vp

Vp

1(104-106

1(20-1(3

1(20-1(4

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DISSECTION OF V{3 REGIONS IMPORTANT FOR INTERACTION WITH SUPERANTIGENS There is a strong association between the TCR Vp element expressed by particular T cells and the ability of these T cells to interact with particular superantigen/MHC complexes. The other variable components of the TCR apparently contribute little to the interaction. Indeed, the soluble isolated p-chain of the TCR is sufficient to bind cells coated with the toxin super antigen SEA ( 1 3 1 ). This Vp/Superantigen association is in marked contrast to the T-cell recognition of conventional peptide antigens presented by MHC molecules, which involves all the variable elements of the TCR (7-9). We have begun studies to dissect the molecular interactions between the components of the trimolecular complex of superantigen, TCR, and MHC class-II molecules, and to examine the structural motifs important in these interactions. The analyses of the Vp repertoire of natural populations of wild mice ( 1 32) recently provided clues that have led us to propose that the self superantigen Mls- l a interacts with a site on the Vf3 element of the TCR that is well away from the predicted complementarity determining regions (CDRs). The CDRs are thought to interact with the complex of con ventional peptide antigen and MHC. Among the wild mice studied several animals expressed variant Vf38.2 elements not previously seen among laboratory inbred strains. Unex pectedly, these Vp8.2 elements (Vp8.2b and VpS.2c) conferred Mis-I" reactivity upon the T cells that bore them. To follow up this observation, the p-gene from a non-MIs-reactive Vp8.2a+ T hybrid was altered using site directed mutagenesis, converting the residues from those expressed by the Vf38.2a allelle found in laboratory strains to those expressed by the wild mice. Mutations 22Asn -+ Asp and 70Glu -+ Lys/71 Asn -+ Glu were shown to contribute to Mls- l a reactivity (133). These residues were oriented on a three-dimensional model based on the known structure of immunoglobulin ( 1 34), an analogous antigen specific receptor, since there is currently no structure available for the TCR. This model predicts that the residues that confer Mis- I " reactivity are on the solvent-exposed surface of a fJ-pleated sheet that forms part of the frame work of the Vp element, distant from the regions that are predicted to interact with peptide/MHC complexes. Recently, Cazenave et al ( 1 35) have also studied VfJ elements expressed by wild-derived mice. By Southern blot analyses they found that several of these mice carry a V/3 1 7 gene with a restriction fragment length poly morphism like that found in SJL, a strain that expresses a functional VfJ 1 7a gene. V/3 1 7a+ T cells are eliminated in (SJL x BALB/c)F, mice due to



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their reactivity to a self-superantigen complexed with IE. However, despite self-superantigen and IE expression, many of the wild-derived mice had significant numbers of peripheral V/3 1 7 + T cells. Sequence analyses of the Vp 1 7 gene from the wild-derived strain, PWK, showed two amino acid residues that differed from the VPI7 sequence of SJL. One of these sub stitutions, GIn � Arg, is in the same position as the Asn � Glu sub stitution present in the Mls-I a reactive Vp8.2c+ TCRs. The other was a Asn _ Ser substitution that would be predicted to lie in the second CDR. Although these authors have not yet determined which of these sub stitutions is responsible for destroying reactivity to the superantigen/IE complex, their data suggest that the superantigen interaction site on the VpI 7 element is also on the side of the TCR away from the CDRs. Since VfJ8 .2 residues that conferred reactivity to the self-superantigen Mls- l a had been identified, it was of interest to see whether residues in the same region of the TCR were critical for the interaction with the S. aureus toxin superantigens. Choi et al ( 1 36) observed that human T cells bearing the closely related Vp elements 1 3. 1 and 1 3.2 showed different response patterns to S. aureus toxins. Murine T-cell hybrids transfected with murine/human chimeric TCR p-genes were used to demonstrate that resi dues predicted to lie on a p-pleated sheet on the side of the p-chain contributed to SEC2 and SEC3 reactivity. All these data support the model that both the self- and foreign super antigens interact with a site on the V /3 element of the TCR which is distinct from the region of the receptor thought to be responsible for peptide antigen/MHC recognition ( 1 1 9). Moreover, this model is consistent with the observation that there is no correlation between expression of Va elements and reactivity to superantigens ( 1 37).

FUNCTIONAL SITES ON THE TOXINS Information is, at present, limited on the structural basis for SE interaction with MHC or TCR Vp. Evidence that the intact molecule is needed for mitogenicity comes from demonstrations that SEB lost function after enzymatic cleavage ( 1 38). Although many SEs contain a conserved di sulfide loop, conclusions drawn from experiments with SEB suggest that this structural feature is not necessary for their biologic activity (58, 1 38, 1 39). In addition, the absence of this disulfide linkage in TSST- l , ExF, and the SPEs would argue against a crucial role for the disulfide loop in superantigenicity (70, 72, 84, 1 40). Investigations on the effect of frag mentation of TSST- 1 indicate that the N-terminal 88 amino acids are dispensable for biologic activity ( 1 41). Other experiments have employed chemical methods to modify specific amino acid residues in TSST- l .


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Results from such studies have indicated that some histidine and tyrosine residues are important for toxin biologic function ( 1 42). This has been exploited by Blanco et al (\30) who have studied the role of several His and Tyr residues in TSST- I using site directed mutagenesis. Nine of the fourteen His or Tyr residues of TSST- 1 were examined for their effect on the ability of the toxin to stimulate murine splenocytes. While several of the mutants did not significantly differ from the wild type toxin, the alteration of residues in the C-terminal third of TSST-1 did dramatically affect the mitogenicity of the toxin. The modified SE molecules described thus far have not been examined systematicalIy for their ability to bind to MHC or interact with TCR. In contrast, experiments by Johnson and colIeagues ( 1 43) using synthetic peptides suggest that the N-terminal 27 amino acids of SEA play a role in its binding to MHC class II. It is perhaps premature to conclude that these regions are responsible for SE superantigenicity since analyses with SEB mutants that have reduced abilities to interact with class II or TCR show that other regions of the toxin are important for its function as a superantigen (J. W. Kappler, unpublished observations). Carlsson et al (93) have shown that very few SE molecules need to be bound to a class II-positive cell for it to trigger a T-cell response. They estimated that only five SEA or SEB molecules per cell were capable of inducing half maximal activation . The question of whether the binding of SE molecules to class II leads to conformational changes, or to modi fication of MHC or TCR, is currently unresolved.

WHAT ARE MLS DETERMINANTS? Nothing at alI is known about the structure ofthe MIs determinants despite nearly 20 years of study. Their characteristic properties of interacting with MHC class II and TCR V/3 suggest that they may have structural similarities with the bacterial toxins that also display these properties. Despite multiple attempts, antibodies have not been raised against the MIs determinants, and immunoprecipitation of self-superantigens along with class II molecules has thus far proved unsuccessful. Over the years several suggestions have been put forward to explain the functional characteristics of the MIs determinants and the other self-superantigens. Webb et al (\44) suggested, for example, that Mls- I a is a T-cell mitogen that interacts with a receptor distinct from the a/3TCR. This hypothesis is difficult to reconcile with the many reports of TCR V/3 association with the self-superantigen Mls-I a. Janeway and coworkers ( 1 9) initially pro posed that Mls-\ was an adhesion strengthening molecule expressed on antigen presenting celIs which enhanced their interactions with T cells.



76 1

More recently they coined the term "co-ligand" to describe this sort of protein that is intimately associated with class-II molecules on the surface of B cells and that can also bind to TCR V[3 elements (1 1 9). Marrack & Kappler suggested that the MIs gene products might modify MHC class-II proteins by covalent modification, perhaps by the addition of carbohydrate, or alternatively, that the MIs genes may encode peptides that could bind class-II molecules, or proteases responsible for the pro cessing of such peptides (1 45). The recent data suggesting an interaction site for superantigens on the TCR V[3 element well away from the CDRs (1 33, 1 36), and the demonstration that mutations in class II that affect T cell responses to peptides do not affect responses to toxins (94, 95), make this last possibility unlikely. Alternatively the MIs phenotypes may represent differences in mobility of the lipid components of accessory cell membranes ( 1 46, 1 47). None of these possibilities can be totally discounted until the self-superantigen genes and their products have been identified. However, we currently favor the hypothesis that the self-superantigens are proteins that interact with a region on the surface of one of the fJ-pleated sheets of the VfJ domain of the TCR and with the MHC class-II molecule. A schematic illustration of how we envisage the trimolecular complex of Superantigen-TCR MHC class-II is shown in Figure 1 .

SOME EVOLUTIONARY SPECULATION It is striking that the endogenous murine superantigens and the bacterial toxin superantigens have similar modes of stimulating T cells; that is, they bind to a variety of different MHC class-II molecules and interact with T cell

Antigen Presenting Cell Figure 1

class II.

Schematic representation ofthe trimolecular complex ofSuperantigen-TCR-MHC

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the V{3 element of the TCR. Currently an open debate flourishes over the evolutionary relationship between the host superantigens and the bacterial toxins. Whether the self-superantigens or the bacterial toxins came first seems rather like the question of the chicken and the egg.


Why Do Bacteria Use Superantigens? At first glance, SE stimulation of large numbers of T lymphocytes might seem disadvantageous to the invading microorganism. However, the release of large amounts of Iymphokines by the activated cells ( 1 48-1 50), and the swamping out of directed responses by the overwhelming T-cell proliferation could contribute to an immunosuppressive state and favor the bacteria. In fact, many of the foreign superantigens have been shown to be immunosuppressive ( 1 03, 1 5 1 - 1 53). Marrack et al (103) have shown that the toxicity of SEB is a function of its ability to stimulate T cells in a V/3 specific manner and that mice that deleted SEB-reactive T cells before they reached the periphery were not intoxicated by SEB. Additionally, the ability of SEs to activate effector cytotoxic T cells ( 1 25, 1 27, 1 54) suggests an even more insidious mechanism for bacterially induced immunosuppression. The activation of numerous cytotoxic T cells in vivo could lead to the destruction of class II-expressing antigen presenting cells that have bound SE molecules. Such a scenario could prevent the host from mounting a concerted immune response after the loss of the essential, MHC class-II bearing, antigen-presenting cells. These conjectures would argue that the bacteria retain SEs and strive to evolve toxins that bind to a large array of MHC class-II molecules and V{3 elements. Such evolutionary pressure might be reflected in the observation that the SEs of S. aureus, a human pathogen, have a much higher affinity for human class-II molecules than for murine Ia antigens (86). Further, the ability to transfer toxin genes rapidly between bacteria would be aided by the fact that several superantigen genes are encoded on mobile genetic elements (59). One might speculate that the bacteria have exploited the host's need to conserve certain V{3 and class-II sites for some unknown function. Janeway ( 1 1 9) has proposed that self-superantigens serve as co-ligands essential for proper T cell function, and foreign superantigens may have evolved to exploit this required mechanism. He has speculated that the bacteria could have acquired the self-superantigen (or co-ligand) genes from their hosts and that these genes may have mutated to give rise to the toxins that maintain their ability to bind M HC class-II molecules and the V{3 element of the TCR ( 1 55). How the bacteria could have picked up the host genes is unclear, since the DNA of the bacteria and the host does not come into contact during their life cycles.



Why

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Do Mice Use Self-Superantigens?

Marrack & Kappler (132, 156) have proposed that mice use structures analogous to toxins to protect themselves from the toxic effects of the bacterial superantigens. Mice lacking T cells bearing toxin-reactive V{3s are resistant to the pathological effects of the toxins (103). To explain the great flexibility of the V{3 repertoires of individual wild mice, due both to V{3 gene deletions and to elimination of T cells bearing self-superantigen-reactive V{3 elements, Pullen et al (132) hypothesized that mice maintain flexibility in their T-cell repertoires as a result of balancing selection. On the one hand it would be advantageous for mice to have T cells expressing as many different TCRs as possible to facilitate responses to a wide variety of potential pathogens, while on the other hand surviving an infection by toxin-secreting bacteria may necessitate a TCR repertoire lacking certain toxin-reactive V{3 elements. The elimination of subsets ofT cells bearing certain V{3 elements reactive with self-superantigens provides the mouse population with the necessary flexibility. Self-superantigens are encoded by genes unlinked to the TCR and MHC loci and are thus inherited independently. Since the products of only one copy of the superantigen gene cause elimination of reactive T cells, from generation to generation there are potentially huge shifts in the T-cell repertoire. For example, two mice lacking V{36, 7, 8.1, and 9-bearing T cells due to their expression of the Mls-I ajMls-l b genotype can generate progeny homozygous for the nonstimulatory Mls-I b allele that express a full complement of T cells bearing Mls- l a-reactive V{3 elements. Elimination of self-superantigen-reactive T cells during tolerance induc tion in the thymus plays an important role in shaping the T-cell repertoire (12). It influences the dominant V{3 elements used in responses to con ventional peptide antigens (157). Not only is this skewing of the repertoire potentially important for protection against the effects of the bacterial toxins (103), it may also determine susceptibility to a variety of auto immune disorders for which a dominant V{3 association has been described (158-162). Mouse strains that eliminate all T cells bearing self-super antigen-reactive V{3 elements may be protected from the consequences of these cells reacting to autoantigens not expressed in the thymus but encountered later in life in the periphery. Heber-Katz and Acha-Orbea (163) have noted that T cells responsible for inducing autoimmune conditions including experimental autoimmune encephalitis in mice and rats frequently use a common V/3 element, V/38.2. It is conceivable that the binding of this TCR V{3 element to a bacterial product or self-antigen on peripheral tissues may be sufficient to trigger these T cells to initiate the pathogenesis of autoimmune disease. Some


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circumstantial evidence implicates some foreign superantigens in auto immune disorders. Several microorganisms that produce superantigens have been linked to autoimmune sequelae after bacterial infections (6 1 , 62). It is not only the TCR that has the ability to bind bacterial products at a site distinct from the conventional antigen binding site. Mammalian immunoglobulin heavy chains have conserved amino acid residues on a solvent-exposed face of a [3-pleated sheet in the variable region (VH) that is equivalent to the region on the TCR V[3 element implicated in the interaction with both self- and foreign superantigens ( 1 33, 1 36, 1 64). This conservation is strongest among members of the V H3 subgroup of anti bodies that have also retained the ability to bind Staphylococcal Protein A ( 1 65). These antibodies are heavily represented in the fetal repertoire of mice and humans, and among autoantibodies of germline sequence. The evolutionary advantage offered by this binding of TCRs and immuno globulins to bacterial products, and potentially to self-antigens, remains obscure.

Are Se/f-Superantigens Encoded By Viral Genes? An exciting possibility to be considered is that the self-superantigens may be products of retroviral integrants that are scattered throughout the mouse genome. Woodland et al ( 1 09) have mapped the gene encoding one of the self-superantigens, which combines with IE and interacts with V[35 and I I -bearing T cells, to a position closely linked to the mouse mammary tumor virus integrant, M tv-9, on chromosome 1 2. Extensive analysis of recombinant inbred strains and the progeny of a backcross have thus far yielded no recombinants between the self-superantigen (or IE T cell cotolerogen) Etc- I and Mtv-9. Their data map these loci to less than one centimorgan apart (D. L. Woodland, E. Palmer, manuscript in prep aration). Although this could be equivalent to at least 1 000 kb of DNA, it is formally possible that this superantigen is encoded by Mtv-9, or that it is the product of a gene under the control of the Mtv-9 promoter. Mls- 1 is also linked to a retroviral integrant, Mtv-27, on chromosome 1 ( 1 66). However, it should be noted that recombinants between M ls-2a and M ls-3" and the nearest known retroviral markers have been reported ( 1 2, 1 07). Recently we detected a new se1f-superantigen that deletes V[3 1 4-bearing T cells (P. Marrack, E. Kushnir, J. W. Kappler, manuscript submitted). This superantigen is maternally transmitted in the milk of C3H/HeJ mice. Excitingly, there is a correlation between deletion of V[31 4+ T cells and transmission of exogenous mammary tumor virus (MTV) in the milk


765

of C3H substrains. This suggests that this superantigen may indeed be encoded by a retrovirus.


Do Humans Express Self-Superantigens? Self-superantigens have not been documented in humans, and self-super antigens may be restricted to rodents. However, in light of the parallels between murine and human Vp-specific responses to foreign superantigens, and the pivotal role that self-superantigens appear to play in shaping the T-cell repertoire of Mus musculus domesticus, it is possible that thus far they may simply have escaped detection. The outbred nature of human populations makes any genetic analyses of these multigenic phenomena extremely cumbersome. Moreover, since mice have approximately 20 Vp gene segments (99), and humans have approximately 50 ( 1 67), stimulation ofT cells bearing an individual human Vp element would be potentially much more difficult to detect in a mixed leucocyte culture than was the case for Festenstein's original discovery of MIs-stimulation in a murine M LR. It may be possible to detect the presence of self-superantigens in humans by the absence of peripheral T cells bearing particular Vps. This procedure was used to great advantage in studying the shaping of the murine T-cell repertoire by tolerance to self-super antigens, and the availability of increasing numbers of monoclonal antibodies specific for human TCR Vp elements should yield exciting information. Literature Cited

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and biological aspects of in vitro lym phocyte allotransformation (MLR) in the mouse. Transp/. Rev. 1 5 : 62-88 2. Spero, L., Johnson-Winger, A., Schmidt, J. 1 . 1 988. Enterotoxins of Staphylococci. In Handbook of Natural Toxins, ed. C. M . Hardegree, A. T. Tu, pp. 1 3 1-63. New York: Dekker 3. Peavy, D. L., Adler, W. H . , Smith, R. T. 1 970. The mitogenic effects of endo toxin and staphylococcal enterotoxin B on mouse spleen cells and human peripheral lymphocytes. J. Immunol. 1 05: 1 453-58

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of mature T cells and clonal deletion in neonatal mice. Cel/ 56: 27-35 6. Kronenberg, M., Siu, G., Hood, L., Shastri, N. 1 9 86. The molecular gen etics of the T cell antigen receptor and T cell antigen recognition. Annu. Rev. 7.

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Fink, P., Matis, L., McElligott, D., Bookman, M., Hedrick, S. 1 986. Cor relations between T cell specificity and structure of the antigen receptor. Nature 32 1 : 2 1 9-26

Winoto, A., Urban, J., Lan, N., Gover man, J., Hood, L., Hansburg, D. 1 9 86. Predominant use of a VIX gene segment in mouse T-cell receptors for cyto chrome c. Nature 324: 679-82 9. Danska, J. S., Livingstone, A. M . , Paragas, V., Ishihara, T., Fathman, C . G. 1 990. The presumptive CDR3 regions of both T cell receptor C! and f3 chains determine T cell specificity for myoglobin peptides. J. Exp. Med. 1 72: 8.

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10. Kappler, J. W., Staerz, U., White, J., Marrack, P. C 1 988. Self-tolerance eliminates T cells specific for MIs-modi fied products of the major histo compatibility complex. Nature 332: 3540 I I . MacDonald, H. R., Schneider, R., Lees, R. K., Howe, R. C., Acha-Orbea, H., Feste n stein, H . , Zinkernage1, R. M . , Hengartner, H. 1 988. T-cell recep tor Vf3 use predicts reactivity and tol erance to Mlsa-encoded antigens. Nature 332: 40-45 1 2. Pullen, A. M., Marrack, P., Kappler, J. W. 1 9R8. The T cell repertoire is heavily influenced by tolerance to polymorphic self antigens. Nature 335: 796-801 1 3 . Wil son, D. B., Blyth, J. L., Nowell, P. C 1 968. Quantitative studies on the mixed lymphocyte interaction in rats. III. Kinetics of the response. 1. Exp. Med. 1 28: 1 1 57-8 1

MIs" and M I s . 1. In press 22. Click, R. E., Adelmann, A. M . , Azar, M. M . 1 985. Immune responses in vitro. XIII. M LR detectability ofMls'-, MIsb_, M lsC_ and Mlsd_ encoded prod ucts. J. Immunol. 1 34: 2948-52 23. Abe, R., Ryan, J., Finkelman, F., Hodes, R. 1987. T cell recogni ti on o f MIs. T cell clones demonstrate poly morphism between Mlsa, Mlsc, and MIs . J. Immunol. 1 38: 373-79 24. Webb, S., M olnar-Kimber, K . , Bruce, J., Sprent, J., Wilson, D. 1 98 1 . T cell clones with dual specificity for MIs and various major histocompatibility com plex determinants. J. Exp. Med. 1 54: from prototypic

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25. Molnar-Kimber, K. L., Sprent, 1. 1 98 1 . Evidence that strong Mis determinants are nonpolymorphic. Transplantation 3 1 : 376-78

14. Janeway, C, Lerner, E., Jason, J., .lones, B. 1 9RO. T lymphocytes respond ing to mIs-locus antigens are Iyt- I + 2 � and I - A restricted. Immunogenetics 1 0 : 48 1-97 1 5 . Lutz, C. 1., Glasebrook, A. L., Fitch, F. W. 198 1 . Enumeration of aIlo reactive helper T lymphocytes which cooperate with cytolytic T lympho cytes. Eur. J. Immunol. I I : 726-34 16. Mi ller, R. A., Stutman, O. 1 982. Esti mation of IL-2 secreting helper T cells by limiting dilution analysis, and dem onstration of unexpectedly high levels of I L-2 production per responding cell. J. lmmunol. 1 28: 2258-64 1 7. Festenstein, H. 1 974. Pertinent features of M locu s d,,[t:rminan[s induding revised nomenclature and strain dis tribution. Transplantation 1 8 : 555-

26. Jones, B., Janeway, C 1 982. MHC rec ognition of clones of MIs specific T lymphocytes. Immunogenetics 1 6: 24356 27. Glasebrook, A., Fitch, F. 1 980. Allo reactive cloned T cell lines. I. Inter actions between cloned amplifier and cytolytic T cell lines. J. Exp. Med. l S I : 876-95 28. Abromson-Leeman, S. R., Laning, 1 . C , Dorf, M . E. 1 988. T cell recognition of MIse.> determinants. J. Immunol. 140: 1726-3 1 29. Abe, R., Ryan, J . , Hodes, R. 1 987. Clonal analysis of the MIs system. A reappraisal of polymorphism and allel ism among Mlsa, MIs', and Mlsd . J.

18. Festenstein, H., Bishop, C , Taylor, B. 1977. Location of MIs locus on mouse chromosome I . Immunogenetics 5: 35761 19. Janeway, C J r . , Katz, M . 1985. The immunobiology of the T cell response to MIs-locus-disparate stimulator cells. I. Unidirectionality, new strain com binations, and the role of Ia antigens. J. Immunol. 1 34: 2057-63 20. Coutinho, A., Meo, T., Watanabe, T. 1 977. Inrlependent segrega tion of two functional markers expressed on the same B-cell subset in the mouse: the MIs determinants and LPS receptors. Scand. 1. lmmunol. 6: 1 005-12 2 1 . Ryan, J. J., LeJeune, H. B. 1 990. Func tional demonstration of a newly defined and widely distributed member of the MIs superantigen family, distinct

7: 683-708 3 1 . Peck, A. B . , Janeway, C. A., Wigzell, H. 1 977. T lymphocyte responses to Mis locus antigens involve recognition of H-2 1 region gene products. Nature 266: 840-42 32. Janeway, C A., Conrad, P. J., Tite, J. P., Jones, B., M urphy, D. B. 1 983. Efficiency of antigen presentation dif fers in mice differing at the MIs locus. Nature 306: 80-82 33. Debreuil, P. C, Caillol, D. H . , Lemonnier, F. A. 1982. Analysis o f unexpected inhibitions o f T lympho cyte proliferation to soluble antigen, a\loantigen and mitogen by unfrag men ted anti-IN or anti-IEjCk monoclo nal antibodies. J. Immunoqenet. 9: 1 1-24 34. Katz, M . , Janeway, C. .If. 1 9R5. The

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