Ann M. Pullen

Identification of the region of T cell receptor β chain that interacts with the self-superantigen MIs-1a

Superantigen-MHC complexes are known to stimulate T cells primarily via the V beta element of the T cell receptor. In this paper we identify a number of amino acid residues that define the region of a particular V beta element interacting with one of the self-superantigens, MIs-1a. These residues are predicted to lie on a beta-pleated sheet of the T cell receptor, away from the complementarity determining regions of the receptor, which are thought to interact with complexes of conventional peptide antigens and MHC. In support of this prediction, mutations affecting MIs-1a activity have no effect on the response to conventional antigen and MHC.

The Bacterial and Mouse Mammary Tumor Virus Superantigens; Two Different Families of Proteins with the Same Functions

In conclusion, the bacterial toxins are completely unlike the MTV superantigens in primary sequence and structure. The former are soluble globular proteins which do not have to be proteolytically cleaved before they act. The latter are synthesized as type II membrane proteins and may be clipped before they reach the cell surface and act to stimulate T cells. Table III summarizes the similarities and differences between the two sets of superantigens. The most notable quality of these molecules is that both sets of families have developed strategies whereby they bind to Class II and engage V beta. As far as the microorganisms which produce them are concerned, these two properties appear to be essential since they are absolutely conserved over proteins of a number of different structures. Several questions can now be addressed as follows. a. Why do all known superantigens bind to Class II? For the microorganism which produces them, the function of superantigens appears to be T-cell and perhaps directly or indirectly B-cell and macrophage stimulation. Activation of virgin T cells requires engagement with antigen plus MHC on professional antigen-presenting cells. Unlike other cell surface proteins, for example Class I, most Class II in animals is expressed on such cells. Therefore it is likely that superantigens have evolved to engage Class II because presentation to T cells by Class II-bearing cells offers the superantigen the best chance of activating its target T cells. b. Why do superantigens engage TCR V beta and not V alpha or CD3? It is possible that superantigens bind to the V beta portion of the TCR rather than V alpha because the latter does not have a consistently well exposed face for engagement. The fact that it is perhaps relatively easier to produce anti-V beta rather than anti-V alpha antibodies supports this idea. We have shown that N-glycosylation of V beta can interfere with recognition by vSAGs (Pullen et al. 1991), perhaps glycosylation of V alpha tends to conceal otherwise available sites. As far as C beta, C alpha or CD3 engagement is concerned, this may be just too dangerous for MTVs. The role of MTVs SAgs in the life history of the virus seems to be to stimulate T cells in the suckling recipient and thereby create a pool of activated lymphocytes in which the virus may survive until the mouse gives birth and transmits the virus to her own progeny (Hainaut et al. 1990, Golovkina et al. 1992).(ABSTRACT TRUNCATED AT 400 WORDS)

Tolerance to self antigens shapes the T-cell repertoire.

The mechanisms of thymic selection and self tolerance are essential to the generation of the T-cell repertoire but are still poorly understood. It is thought that T cells bearing aP receptors with potential to recognise a peptide fragment of foreign antigen bound to a self major histocompatibility complex (MHC) molecule are selected by weak interaction with self-MHC on thymic epithelial cells (Zinkernagel et al. 1978, Bevan & Fink 1978, Kruisbeck et al. 1985, Lo et al. 1986, McDuffie et al. 1986, Farr et al. 1985, Bom et al. 1987), whilst those capable of recognising self molecules alone are eliminated upon interaction of their receptors with MHC on bone marrow-derived cells (Jenkinson et al. 1985, Lo et al. 1986, von Boehmer & Schubiger 1984, Marrack et al. 1988). Generally the frequency of T cells reactive with a particular foreign antigenMHC complex is low; however, the artificial system of the mixed lymphocyte reaction (MLR) has been used to show that the frequency of T cells reactive to allogeneic MHC is high (Wilson et al. 1968, Bach et al. 1972, Schreffler & David 1975), whilst the frequency is even higher for the products of the Mis loci (Festenstein 1973, 1974, von Boehmer & Sprent 1974, Schirrmacher et al. 1975). Three possible mechanisms for T-cell tolerance have been proposed (reviewed by Nossal 1983): clonal anergy which involves the inactivation of responding T cells (Nossal & Pike 1981), clonal suppression involving suppression by other Tcell clones (Gershon & Kondo 1971) and clonal deletion. The production of monoclonal antibodies with specificity for particular T-cell receptor variable elements has facilitated the recent demonstrations that self-reactive T cells are eliminated in the thymus (Kappler et al. 1987b, .1988, MacDonald et al. 1988,

T Cell Repertoire and Tolerance

Publisher Summary This chapter discusses T-cell repertoire and tolerance. Murine αβ Τ-cell receptors (TCRs) have five variable segments: Vα and Vβ (variable), Dβ (diversity), and Jα and Jβ(joining). Additional variability is provided by imprecise joining of these gene segments and the inclusion of additional nucleotides at the junctions. All five variable segments contribute to a binding site for complexes of peptide antigen with major histocompatibility complex (MHC) products. Thymocytes bearing receptors which interact with self-MHC during development in the thymus are selected to mature. In mice that express Mls/class II complexes, T cells bearing reactive Vβ elements are clonally eliminated during development in the thymus. Similar phenomena have been described for T cells bearing TCRs reactive with moieties combined with IE molecules. A quarter of the wild mice included in a study described in the chapter were homozygous for an extensive Vβ gene deletion on chromosome 6. The deletion included 11 Vβ genes and so reduced the extent of the repertoire to less than half that of a mouse carrying the full complement of Vβ genes. All the wild mice analyzed had no Vβ 17a+ T cells. They carried a restriction fragment length polymorphism indicative of a point mutation that results in a premature stop codon in the Vβ 17b gene.

The Advantages of Limiting the T Cell Repertoire for Antigen & MHC

T cell receptors are made up of two polypeptides α and β, which are constructed in each cell by rearrangement of one of a number of V (variable), D (diversity) and J (joining) gene segments. The inclusion of nucleotides not encoded in the germline, or the exclusion of germline nucleotides, at the V-J junction also adds to the number of possible receptors. The tremendous flexibility which this type of construction allows has been well established for immunoglobulins and T cell receptors and many millions of combinations are possible. Besides the well known processes of thymic positive and negative selection, mice use a number of strategies to reduce the enormous T cell receptor repertoire available to them. In this paper these strategies will be outlined and their possible advantages will be discussed.