Tyrosine phosphatase CD45 is essential for coupling T-cell antigen receptor to the phosphatidyl inositol pathway

Article Abstract:

Many cells throughout the body are strongly influenced by their cell-surface receptors, and yet little is known about the mechanisms by which surface stimulation is translated into intracellular changes. Cells of the immune system are unique in that they respond to contact on their cell-surface receptors with foreign antigens. This action initiates a series of events which lead to an immune response. In the case of T-cells, the initial foreign antigen contact results in the activation of an enzyme called tyrosine kinase and the generation of 'second-messenger' molecules whose increasing presence within the cell initiates a cascade of other events. When T-cells are stimulated, the second-messengers are derived from phosphatidyl inositol. To determine the sequence of events which lead tyrosine kinase activation and second-messenger synthesis, researchers screened T-cell lines derived from patients with leukemia. Abnormal cells were isolated, which were found to be lacking a particular cell surface molecule called CD45. The cells were then used to examine T-cell stimulation; it was found that when stimulated, these cells failed to produce phosphatidyl inositol second messengers. To rule out the possibility that this observation could be the result of other, unknown, abnormalities of the cell line, it was necessary to restore CD45 expression to these cells to see if the T-cell stimulation proceeded as normal. This was accomplished using the techniques of molecular biology, and it was found that normal stimulation was indeed restored. The results show that CD45, a cell-surface molecule which has enzymatic tyrosine phosphatase activity inside the cell, plays a key role in coupling events at the T-cell receptor and second-messenger molecule synthesis. (Consumer Summary produced by Reliance Medical Information, Inc.)

Lymphocytes

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Residues of the variable region of the T-cell receptor beta-chain that interact with S. aureus toxin superantigens

Article Abstract:

The T-cell receptor is a molecule on the surface of T-cells which recognizes specific antigens in the form of processed peptide fragments presented to the T-cells by molecules of the major histocompatibility complex (MHC). The T-cell receptor has alpha and beta chains, both of which have variable regions; both variable regions contribute to the T-cell receptor's ability to recognize a wide variety of antigens. However, some antigens seem to be able bind to the MHC molecules without being processed, and to stimulate all T-cells that have certain variable-region elements on the beta chains, regardless of what variable elements are present. Such antigens are called 'superantigens'; the toxins produced by the infectious bacteria Staphylococcus aureus are examples of such superantigens. To probe the molecular basis for the binding of superantigens to beta chains, researchers have developed a composite mouse-human model. When T-cells from mice were transfected with genes for different beta chains, it was found that the mouse T-cells were capable of producing a T-cell receptor that had human beta chains, but were otherwise characteristic of mouse. Furthermore, the resulting hybrid receptor proved to be fully functional and could be stimulated with superantigen. As a result, the investigators could grow as much of the mouse T-cells as they wanted, and could obtain sufficient receptors for a careful analysis of why some beta chains bind some toxin superantigens and others bind different superantigens. Based on this data, the authors propose a model for superantigen binding by the T-cell receptor. (Consumer Summary produced by Reliance Medical Information, Inc.)

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The alpha 1 domain of the HLA-DR molecule is essential for high-affinity binding of the toxic shock syndrome toxin-1

Article Abstract:

Some protein toxins excreted by the bacteria Staphylococcus aureus have the ability to act as superantigens. That is, they bind directly to the molecules of the histocompatibility complex without being processed into peptides within the antigen-presenting cell. They then stimulate any T-cell that has the appropriate sequence in the beta chain in its T-cell receptor, regardless of the composition of the rest of the beta or alpha chain. These superantigens include TSST-1, which is thought by some to be involved in toxic shock syndrome. To determine how these superantigens bind to molecules of the MHC without being processed, investigators transfected mouse cells with the genes for human class II histocompatibility molecules DR and DP. The investigators examined the ability of TSST-1 to bind to chimeric molecules. That is, they created mouse cells with DR alpha chain or DP alpha chain. The beta chains were then supplied as natural DR beta or beta chains that were part DR and part DP. The only factor that was found to be necessary was the presence of the DR alpha chain. If the DR alpha chain was present, the resulting MHC molecules bound the toxin; if the alpha chain was from the DP molecule, the toxic shock syndrome toxin-1 did not bind. (Consumer Summary produced by Reliance Medical Information, Inc.)

Major histocompatibility complex, HLA class II antigens

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