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Although superantigens and their molecular interactions with MHC class II molecules have been well characterized recently, little is known concerning the physiological function of different types of APC in inducing superantigen-mediated T cell activation. To evaluate the potential of nonhematopoetic cells to present superantigens to T cells, we have tested astrocytes as a typical "nonprofessional" APC. Although astrocytes can express appropriate levels of MHC class II products and adhesion molecules, they turned out to be unable to mediate superantigen-driven activation of normal T lymphocytes, even in the presence of rather high concentrations of toxins. In contrast, they could properly present equimolar amounts of nominal Ag to various Ag-specific T cell lines under the same experimental conditions. Inability of astrocytes to support T cell responses to superantigens could not be overcome by addition of cytokines IL-1 and IL-6. Binding studies with class II-expressing astrocytes revealed that T cell unresponsiveness was not due to a general failure of astrocytes to bind the superantigen. Moreover, the resulting SA-class II complex was recognizable by TCR, as demonstrated by the capacity to activate IL-2 secretion in T cell hybridomas. Our results extend previous studies demonstrating marked differences of various types of APC to trigger T cell responses to superantigens and describe for the first time a dissociation of the Ag-presenting capacity for peptide-Ag vs superantigen on an accessory cell.Keywords:
Superantigen
MHC restriction
Superantigens (SAGs) are a class of immunostimulatory and disease-causing proteins of bacterial or viral origin with the ability to activate large fractions (5-20%) of the T cell population. Activation requires simultaneous interaction of the SAG with the V beta domain of the T cell receptor (TCR) and with major histocompatibility complex (MHC) class II molecules on the surface of an antigen-presenting cell. Recent advances in knowledge of the three-dimensional structure of bacterial SAGs, and of their complexes with MHC class II molecules and the TCR beta chain, provide a framework for understanding the molecular basis of T cell activation by these potent mitogens. These structures along with those of TCR-peptide/MHC complexes reveal how SAGs circumvent the normal mechanism for T cell activation by peptide/MHC and how they stimulate T cells expressing TCR beta chains from a number of different families, resulting in polyclonal T cell activation. The crystal structures also provide insights into the basis for the specificity of different SAGs for particular TCR beta chains, and for the observed influence of the TCR alpha chain on SAG reactivity. These studies open the way to the design of SAG variants with altered binding properties for TCR and MHC for use as tools in dissecting structure-activity relationships in this system.
Superantigen
MHC restriction
CD74
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Superantigen
MHC restriction
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Superantigen
MHC restriction
Antigen processing
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Superantigen
MHC restriction
CD74
Alpha chain
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T cells bearing certain variable (V) regions of the T cell receptor (TcR), including V beta 3, V beta 6, V beta 8.1 and V beta 9, are stimulated by one or more forms of the endogenous superantigen, mouse lymphocyte stimulatory (Mls) locus, encoded by the mouse mammary tumor virus, in the context of a non-polymorphic region of the class II molecules of the major histocompatibility complex (MHC). To identify putative sites of interaction of TcR-V beta region and Mls-1a, we examined the effect of peptides derived from the protein sequence of V beta 6 on recognition of Mls-1a by T cell hybridomas and show that three peptides corresponding to amino acid positions 1 to 20, 48 to 75, and 58 to 75 of the V beta 6 peptide sequence interfere with the activation of several V beta 6+ hybridomas by Mls-1a-bearing spleen cells, but not with that of a V beta 8+ hybridoma. The Mls-reactive hybridomas are specific for a synthetic peptide poly-18, poly EYK(EYA)5 and its peptide (EYA)5, in the context of I-Ad. This peptide does not require processing and the peptides 1-20, 48-75, and 58-75 do not inhibit recognition of (EYA)5 by the same V beta 6+ T cell hybridomas. The two sequences 1-20 and 58-75 are proposed to lie outside the putative binding domain of processed antigen, indicating that recognition by TcR of Mls-1a is different from the classical MHC-restricted recognition of processed antigen. These results suggest that the recognition of superantigen/class II MHC by T cells can be inhibited by peptides related to the site of interaction of the TcR, suggesting that such peptides could have possible regulatory effects on the induction and regulation of immune responses.
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BETA (programming language)
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Abstract Superantigens (SAg) interact with T lymphocytes bearing particular Vβ sequences as part of their T cell receptor (TcR). The interaction, however, requires the presence of major histocompatibility complex (MHC) class II molecules on antigen‐presenting cell (APC). In peculiar circumstances, MHC class II + T cell clones (TCC) have been shown to present peptides and selected antigens interacting with antigen‐specific TCC in the absence of APC. In this report we studied the capacity of SAg to mediate a T‐T cell interaction, investigating the TCC ability to present a panel of staphylococcal enteroxins (SE) independently of the presence of added APC. Upon exposure to a broad range of SE concentrations, MHC class II + TCC showed an intense proliferative response even in the absence of professional APC. Diverse SE optimally stimulated responder TCC at different concentrations. The proliferation was inhibited by anti‐DR monoclonal antibodies, both in the presence and in the absence of APC. The SE activation of TCC in the absence of APC induced the same series of phenotypic variations as that observed following the TCC stimulation with APC. Irradiated TCC efficiently presented membrane‐bound SE to responder TCC as well as professional APC. These results show that a single cell of a given clone effectively presents the SE to other cells of the same clone, and provide evidence that SAg can efficiently mediate T‐T cell interaction. In addition, the possibility also exists that one cell of the clone can actually undergo an auto‐stimulation via SAg‐mediated interactions between its own TcR and MHC class II molecule. It has recently been suggested that the Vβ‐selective depletion of T cells observed in acquired immunodeficiency syndrome (AIDS) patients might be a consequence of the interaction between a human immunodeficiency virus (HIV)‐encoded SAg and T cells expressing a SAg complementary Vβ. We suggest that the hypothesized HIV‐encoded SAg might mediate T‐T cell interactions that could play a relevant role in the Vβ‐selective depletion of T lymphocytes observed in HIV‐infected patients.
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clone (Java method)
MHC restriction
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Bacterial and retroviral superantigens (SAGs) stimulate a high proportion of T cells expressing specific variable regions of the T cell receptor (TCR) beta chain. Although most alleles and isotypes bind SAGs, polymorphisms of major histocompatibility complex (MHC) class II molecules affect their presentation to T cells. This observation has raised the possibility that a TCR-MHC class II interaction can occur during this recognition process. To address the importance of such interactions during SAG presentation, we have used a panel of murine T cell hybridomas that respond to the bacterial SAG Staphylococcal enterotoxin B (SEB) and to the retroviral SAG Mtv-7 when presented by antigen-presenting cells (APCs) expressing HLA-DR1. Amino acid substitutions of the putative TCR contact residues 59, 64, 66, 77, and 81 on the DR1 beta chain showed that these amino acids are critical for recognition of the SAG SEB by T cells. TCR-MHC class II interactions are thus required for T cell recognition of SAG. Moreover, Mtv-7 SAG recognition by the same T cell hybridomas was not affected by these mutations, suggesting that the topology of the TCR-MHC class II-SAG trimolecular complex could be different from one TCR to another and from one SAG to another.
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Bacterial superantigens can bind TCR in the absence of MHC class II molecules and activate T lymphocytes when cocultured with certain class II-deficient accessory cells. It has not been determined, however, whether these accessory cells provide direct costimulation to the T cell or serve to present superantigens via a nonconventional ligand. We have identified a human adenocarcinoma cell line, SW480, that assists in the activation of human T cells by the staphylococcal enterotoxins B (SEB), C1 (SEC1), and D (SED), but not SEA, SEC2, SEC3, or SEE. SW480 cells did not express class II molecules, and anti-class II mAbs did not inhibit T cell proliferation, supporting the hypothesis that class II is not absolutely required for enterotoxin-mediated T cell activation. The TCR Vbeta profile of T cells stimulated by SEB plus SW480 cells was similar to that of T cells stimulated by SEB plus class II+ APC, indicating that TCR-SEB interactions were preserved in the absence of class II molecules. Binding studies failed to detect specific association of SEB with SW480 cells, suggesting that SW480 cells do not express receptors for enterotoxin. SEB coupled to beads, however, stimulated T cell proliferation, but only in the presence of SW480 cells. SW480 cells express both ICAM-1 and LFA-3 molecules, and the addition of Abs to these receptors inhibited T cell proliferation. These findings support a model in which certain enterotoxins engage the TCR independent of MHC class II or other specific presenting molecules and induce T cell proliferation with signals provided by nonconventional accessory cells.
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MHC restriction
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