S6 Annals of the Rheumatic Diseases 1993; 52: S6-S16 Bacterial and viral superantigens: roles in Ann Rheum Dis: first published as 10.1136/ard.52.Suppl_1.S6 on 1 March 1993. Downloaded from autoimmunity? Hans Acha-Orbea Abstract the cell are presented by MHC class I Superantigens are bacterial, viral, or molecules. Despite the high numbers of retroviral proteins which can activate peptides which can be bound to a particular specifically a large proportion of T cells. MHC molecule, these receptors show striking In contrast with classical peptide antigen specificity for peptides they bind. This recognition, superantigens do not require specificity is due to differences in the amino processing to small peptides but act as acid sequence in the N-terminal part of MHC complete or partially processed proteins. molcules which forms the peptide binding They can bind to major histocompatibility pocket that can accommodate two to four complex class II molecules and stimulate amino acids of the peptide. Specific amino T cells expressing particular T cell acids could be implicated at specific receptor Vp chains. The other poly- localisations in the bound peptides for several morphic parts of the T cell receptor, different MHC class I as well as class II which are crucial for classical antigen molecules. Different MHC class I and class II recognition, are not important for this proteins bind different sets of peptides. Single interaction. When this strategy is used a amino acid differences in this peptide binding large proportion of the host immune region can heavily influence the peptides which system can be activated shortly after can hind to a particular MHC class I or class infection. The activated cells have a wide II molecule. variety ofantigen specificities. The ability The formation of a trimolecular complex to stimulate polyclonal B (IgG) as well as between MHC, peptide, and TCR is highly T cell responses raises possibilities of a specific in that a particular TCR can interact role for superantigens in the induction of only with specific MHC molecules which have autoimmune diseases. Superantigens bound a particular peptide. For this interaction have been a great tool in the hands of TCR and MHC sequences as well as peptide immunologists in unravelling some of the sequences are important. As recognition basic mechanisms of tolerance and occurs almost exclusively with self MHC http://ard.bmj.com/ immunity. molecules, and the same peptides cannot be presented in the context of another MHC (Ann Rheum Dis 1993; 52: S6-S 16) molecule, it is called MHC restricted. This MHC restricted antigen recognition by T lymphocytes leads to formation of a Classical antigen recognition by T cells occurs trimolecular complex between short antigenic by interaction of self major histocompatibility peptides bound to MHC molecules and on October 1, 2021 by guest. Protected copyright. complex (MHC) proteins, which bind small recognition by a TCR (fig IA). fragments of proteins, with T cell receptor In addition to these molecules, a series of (TCR). These three components are briefly other receptors and coreceptors intensify this described below. More detailed information interaction. Most of these intensifying can be found in excellent reviews and the molecules do not contribute to the specificity references therein. 1-6 of the interaction and are not discussed here. The MHC encodes many different proteins. One pair of these coreceptors intensifies the Among these the MHC class I and class II interaction of the TCR with MHC class I molecules are important in this context. These molecules (CD8) or MHC class II molecules dimeric molecules are highly polymorphic in (CD4). Cytotoxic T cells are found amongst the population. Of the order of 50 alleles have the former, and helper T cells amongst the been defined for the different MHC class I and latter. class II molecules. The major function of these The TCR is the end product of a series of molecules is the presentation of antigens to the recombination events during the maturation T cells by acting as receptors able to bind and differentiation of T cells. This brings thousands of 8-9 (MHC class I) or 9-16 together the constant region which is shared (MHC class II) amino acid long processed between all the receptor molecules with the peptides. Such peptides are generated from two or three highly polymorphic parts: variable proteins in the cytoplasm (for MHC class I (V), diversity (D) (in the case of the I chain Ludwig Institute for presentation) or in endosomes (for MHC class only), and junctional (j) elements. These Cancer Research, II presentation) by specialised proteases. Most elements are encoded as V and J clusters, Lausanne Branch, of the antigens entering the cell from the separated but in the same chromosomal 1066 Epalinges, Switzerland outside will be associated with MHC class II localisation as the constant region. In addition, H Acha-Orbea molecules, whereas proteins produced within a tremendous heterogeneity is introduced by Bacteial and viral superantigens S7 A B B cell Ann Rheum Dis: first published as 10.1136/ard.52.Suppl_1.S6 on 1 March 1993. Downloaded from Peptide V' Tcell Tcell Figure 1 Classical peptide and superantigen recognition. (A) In classical antigen recognition a processedpeptide is presented by major histocompatibility complex (MHC) class I or class II molecules to the T cell receptor (TCR). The CD4 or CD8 molecule intensifies this interaction. (B) In superantigen recognition the superantigen crosslinks the TCR V, with MHC class II. It is not known whether antigenic peptides are bound to MHC and whether CD4 and CD8 are of importance. random introduction and deletion of short crystallised structures allows us to suggest a sequences in the V-D, V-J, and D-J regions tentative structure.' 4 These superantigens are during this recombination process. The not processed to small peptides like the functional TCR is composed of an a and a , classical antigens but function as entire chain (which are encoded on different molecules'9-21 (or possibly partially cleaved chromosomes and use different elements), molcules in the case of retroviral and, as only one type of TCR molecule is superantigens, see below). Based on the expressed on one T cell clone, is responsible analysis of MHC class II and TCR mutants for giving the T cell the high specific which lost or gained superantigen binding, recognition capability. In mice there are about as well as the recent crystallisation and 25 Vp, 12 Jp, 75 Va, and 75 JL elements mutagenesis analysis on the bacterial super- encoded. With the introduced random antigen staphylococcal enterotoxin B, it is sequences of the order of 10'5 different TCR now thought that superantigens cross link the molecules can theoretically be produced, by far TCR with MHC class II molecules on the exceeding the potential repertoire of a single lateral side of the complex (fig lB).9-1 21-30 mouse. In humans about 100 Vp elements Recently, with the help of superantigens and exist, whereas the other TCR elements are transgenic mice, direct evidence for two basic similar in number in mice and humans. In tolerance mechanisms (clonal deletion of self http://ard.bmj.com/ humans the V8 families, which are defined by reactive cells in the thymus'3 14 31-36 and 70% amino acid homology, are much larger induction of unresponsiveness (anergy) in the than in the mouse. The number of families is periphery37 38) was produced. In this review comparable. In a classical MHC restricted only the results obtained with superantigens peptide specific T cell response about one in are discussed. 100 000 T cells can interact with one particular T cells mature in the thymus, where they immunogenic peptide-selfMHC complex with learn to distinguish between self and foreign. on October 1, 2021 by guest. Protected copyright. significant affinity. Early in life the immune system is plastic and can adapt to learn what belongs to self and what is foreign. The thymus plays an important Biology ofsuperantigens part in this decision. Cells which are strongly The term superantigen has been given to self reactive are negatively selected (deleted), antigens which can activate of the order of one whereas T cells which can interact weakly with in 10 T cells, allowing the activation of about self MHC molecules are positively selected for 10 000 times more T lymphocytes with a single export into the periphery.33 3' Owing to antigen than in classical MHC-peptide positive selection the cells are trained to recognition.7-12 In contrast with T cell recognise antigens bound to self MHC mitogens, superantigens have a high degree of molecules, as otherwise a large percentage of specificity. T cells which cannot interact with self MIHC It became clear recently that superantigens molecules would be wasted. Negative selection have a new way of interaction with MHC in the thymus (deletion) of 'self reactive' T molecules and the TCR. Instead of interacting cells has been found in mice expressing with the most polymorphic part ofthe receptor, superantigens at birth.7 12-16 I2 With the help of they recognise one or several different TCR Vp monoclonal antibodies specific for Vp regions regions which make only a small contribution of the TCR an almost complete elimination of to the overall heterogeneity. 1318 They can the superantigen reactive V'-bearing T cells interact with MHC molecules and cross link has been noted in mature thymocytes as well the TCR to form an aberrant trimolecular as in the peripheral T cell repertoire. complex (fig lB). Neither the TCR nor the A first encounter with a superantigen in trimolecular complex has yet been crystallised, an adult mouse in vivo leads to an initial but structural homology with previously expansion of the reactive T cells bearing S8 Acha-Orbea one or several specific TCR VP the binding affinities of antibodies to their regions.7 8 12-14 23 43 44 Shortly after this antigen (10-6-10-8 M).