Search PubMed⌕ Search

Biomedical subjects

P Marrack

Publications and source records attributed to P Marrack.

At least 109 records · Page 6Linked to original sources
PubMed1991

Analysis of class II MHC structure in thymic nurse cells.

During the course of thymocyte maturation, the processes of positive selection and tolerance induction are mediated by interactions between thymocyte T-cell receptors and MHC molecules on thymic stromal cells. The means by which these seemingly contrary processes can be mediated by interactions between the same molecules has long been a source of controversy. One idea which has been put forward is that the MHC molecules in different microenvironments of the thymus are not the same. We have tested this hypothesis by examining class II transcripts derived from thymic cortical epithelial cells known as thymic nurse cells, reasoning that alternative splicing of primary transcripts might give rise to a positively selecting MHC molecule. However, we found no evidence for alternative splicing of these transcripts. These results are presented and discussed with regard to implications for possible mechanisms of positive selection.

Amino Acid Sequence↗
PubMed1991

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

Superantigens combine with MHC class-II molecules to form the ligands that stimulate T cells via the V beta element of the T-cell receptor. Two groups of superantigens have been described so far: first, endogenous murine products that include the Mls 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 of T-cell stimulation, and the role that tolerance to self-superantigens plays in shaping the T-cell repertoire. We speculate on the possible evolutionary significance of superantigens.

Animals↗
PubMed1990

Superantigens interact with MHC class II molecules outside of the antigen groove.

Superantigens, including the staphylococcal enterotoxins and the minor lymphocyte stimulatory antigens, are highly potent immunostimulatory molecules, capable of activating virtually all T cells that express particular T cell receptor (TCR) variable regions. Superantigen stimulation of T lymphocytes depends on major histocompatibility complex (MHC) class II molecules, so there has been some debate as to whether superantigens interact with the antigen binding "groove" on class II complexes, just like conventional peptide antigens, or whether they bind elsewhere and serve as TCR coligands. We compared the presentation of peptide antigens and superantigens by a panel of mutant-presenting cell lines, each displaying an A kappa alpha chain with a single alanine replacement along the alpha helix proposed to form one face of the groove. The negligible effect of these 30 mutations on superantigen presentation, versus their drastic consequences for peptide presentation, prompts us to conclude that superantigens interact with MHC class II molecules outside the groove.

Amino Acid Sequence↗
PubMed1990

HLA-DR alleles differ in their ability to present staphylococcal enterotoxins to T cells.

Staphylococcal enterotoxins (SEs) have been shown to bind to major histocompatibility complex (MHC) class II proteins and stimulate T cells in a V beta-specific manner, and these V beta specificities for various SEs have been well documented in mice and humans. This study was undertaken in order to examine the ability of human class II molecules to present SEs to human and murine T cell hybridomas. Using a panel of transfectants expressing individual HLA class II antigens, we have shown that HLA-DR alleles differ in their ability to bind and present SEs. Since the HLA-DR proteins share a common alpha chain, these results indicate that the polymorphic beta chain plays an important role in SE binding and presentation to T cells. In addition, we have shown that human class II isotypes markedly differ in their ability to present SEs. The results of this study should provide information on the region of MHC class II molecules that interacts with foreign, and perhaps self, super-antigens.

Alleles↗
PubMed1990

Selective expansion of T cells expressing V beta 2 in toxic shock syndrome.

Infection with Staphylococcus aureus and the production of toxic shock syndrome toxin-1 (TSST-1) have been implicated in the pathogenesis of toxic shock syndrome. Previous in vitro studies have demonstrated that TSST-1 is a powerful but selective stimulator of human T cells, and that the majority of activated cells express the TCR V beta 2 gene segment. We therefore studied patients with toxic shock syndrome using a modification of the PCR to determine if expansion of V beta 2+ T cells is a marker of the in vivo disease process. Five of eight patients studied demonstrated markedly elevated levels of circulating V beta 2+ T cells, whereas none showed significantly elevated levels of T cells expressing other V beta gene segments. The results suggest that toxin-mediated T cell activation, which involves a large fraction of the human T cell repertoire, may be critical in the pathogenesis of this disease.

Antigens, CD↗
PubMed1990

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

The alpha beta T-cell antigen receptor (TCR) recognizes antigenic peptides in the context of self major histocompatibility complex (MHC) molecules. The specificity of recognition of MHC plus antigen is generally determined by a combination of the variable elements of alpha- and beta-chains of the TCR. Several types of antigen, however, have been identified that, when bound to MHC molecules, stimulate T cells bearing particular variable-region beta-chain (V beta) elements irrespective of the other variable components of the TCR. These have been termed 'superantigens', and here we are concerned with one type of superantigen, the toxins produced by Staphylococcus aureus. T cells have been found that bear closely related members of the same V beta family but respond differently to S. aureus toxins; in particular, cells bearing the human V beta 13.2 element respond to toxin SEC2, whereas cells bearing human V beta 13.1 do not. We have now defined the residues of the V beta element responsible for this difference, and find that they reside in a region thought to lie on the side of the TCR molecule, away from the conventional antigen/MHC-binding site. The evolutionary conservation of this site may be due to its having an important role in some function of the TCR other than the binding of conventional antigen plus MHC.

Amino Acid Sequence↗
PubMed1990

Identification of the region of T cell receptor beta 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.

Animals↗
PubMed1990

The role of the T cell receptor in positive and negative selection of developing T cells.

Although many combinations of alpha beta T cell receptors are available to the T cells in any given organism, far fewer are actually used by mature T cells. The combinations used are limited by two selective processes, positive selection of T cells bearing receptors that will be useful to the host, and clonal elimination or inactivation of T cells bearing receptors that will be damaging to the host. The ways in which these two apparently contradictory processes occur, and the hypotheses that have been suggested to reconcile them, are discussed.

Animals↗
PubMed1990

Normal development of mice deficient in beta 2M, MHC class I proteins, and CD8+ T cells.

Major histocompatibility class I proteins display viral and self antigens to potentially responsive cells and are important for the maturation of T cells; beta 2-microglobulin (beta 2M) is required for their normal expression. Mouse chimeras derived from embryonic stem cells with a disrupted beta 2M gene transmitted the inactivated gene to their progeny. Animals homozygous for the mutated beta 2M gene were obtained at expected frequencies after further breeding. The homozygotes appeared normal, although no class I antigens could be detected on their cells and the animals are grossly deficient in CD4- CD8+ T cells, which normally mediate cytotoxic T cell function.

Animals↗
PubMed1990

A role for clonal inactivation in T cell tolerance to Mls-1a.

Clonal deletion plays a major part in the maintenance of natural self-tolerance in both normal and transgenic mice. Self antigens that are expressed in the thymus result in the physical elimination of autoreactive thymocytes at a particular stage in their development. For example, the majority V beta 6- and V beta 8.1-bearing T cells that recognize the minor lymphocyte-stimulating antigen, Mls-1a (ref. 10) , are clonally deleted in the thymuses of normal mice and transgenic mice expressing Mls-1a (refs 2, 3, 9). In contrast, a very different mechanism of tolerance involving the functional inactivation, but not elimination, of autoreactive cells, termed clonal inactivation or clonal anergy, has been implicated in some experimentally manipulated systems of tolerance. To test further the mechanisms involved in self-tolerance, we have generated transgenic mice expressing a V beta 8.1 beta chain on greater than 95% of peripheral T cells and have tested tolerance to Mls-1a in these mice. Surprisingly, a significant fraction of the CD4+ peripheral cells that survived deletion were non-responsive in vitro to any stimulus tested. Naturally occurring tolerance to a self antigen expressed in the thymus can thus be mediated by clonal anergy, as well as by clonal deletion.

Animals↗
PubMed1990

The staphylococcal enterotoxins and their relatives.

In the article "The staphylococcal enterotoxins and their relatives" by Philippa Marrack and John Kappler (11 May, p. 705), figures 1, 2, and 3 were incorrectly printed. The color portions of figures 2 and 3 should have been included in figure 1. The correct figure 1 is printed below. See image in PDF file

Amino Acid Sequence↗
PubMed1990

The staphylococcal enterotoxins and their relatives.

Staphylococcal enterotoxins and a group of related proteins made by Streptococci cause food poisoning and shock in man and animals. These proteins share an ability to bind to human and mouse major histocompatibility complex proteins. The complex ligand so formed has specificity for a particular part of T cell receptors, V beta, and by engaging V beta can stimulate many T cells. It is likely that some or all of the pathological effects of these toxins are caused by their ability to activate quickly so many T cells. It is also possible that encounters with such toxins have caused mice, at least, to evolve mechanisms for varying their T cell V beta repertoires, such that they are less susceptible to attack by the toxins.

Amino Acid Sequence↗
PubMed1990

Stimulation of B10.BR T cells with superantigenic staphylococcal toxins.

The Staphylococcus aureus enterotoxins are known to be potent T cell activators, stimulating cell proliferation and lymphokine production. Two additional S. aureus proteins, exfoliating toxin and toxic shock syndrome toxin, share these properties. Recently these molecules have been termed "super-antigens" because of their ability to bind to class II MHC molecules and thus form ligands that interact with TCR in an unconventional manner. In this paper we show that each toxin stimulates mouse T cells bearing receptors that include particular V beta regions, almost regardless of the other variable receptor components. In addition, different toxins have different specificities for V beta.

Animals↗
PubMed1990

The toxicity of staphylococcal enterotoxin B in mice is mediated by T cells.

Staphylococcal enterotoxin B (SEB) has been shown in the past to be a potent T cell stimulant in mouse or man. The toxin acts as a superantigen that is, it binds to class II MHC proteins and, as such a complex, stimulates T cells bearing particular V beta s as part of their receptors. The toxin also has several pathological effects, causing, in mice, rapid weight loss, thymus atrophy, immunosuppression, and, at high doses, death. The data in this paper show that at least one of these effects, weight loss, is T cell mediated. Staphylococcal enterotoxin-mediated weight loss is MHC dependent, and is almost absent in animals expressing MHC class II molecules, which, complexed with SEB, are poor T cell stimulants. Also, mice that lack T cell function, genetically or because of cyclosporin A treatment, lose no or less weight than controls in response to SEB. Finally, animals bred such that they express few T cells bearing V beta s with which SEB can interact lose much less weight in response to the toxin than littermate controls that have higher numbers of reactive T cells. It is therefore suggested that the pathological effects of the staphylococcal, T cell-stimulating toxins in mouse and man may be partially or wholly the consequence of massive T cell stimulation.

Animals↗
PubMed1990

Identification of a new cell surface glycoprotein with accessory function in murine T cell responses.

T cell binding to target cells involves not only the TCR and its MHC-bound ligand, but also a collection of additional proteins on both the T cell and its target. In an attempt to identify new molecules involved in this binding, mAb were raised against APC, and screened for their abilities to inhibit T cell recognition of Ag plus MHC on B cells. Six antibodies were identified that inhibited this reaction and that bound a cell-surface glycoprotein (Lgp55), with core polypeptide Mr 30,000 and a glycosylated Mr of approximately 55,000 depending upon the cell source. The properties of Lgp55 were consistent with it being the mouse homologue of a recently identified human ligand (intercellular adhesion molecule-2) for lymphocyte functional Ag-1 because the proteins are of comparable Mr, and antibody to Lgp55, like anti-lymphocyte functional antigen-1, blocks T cell recognition of Ag presented by B cells, but not of Ag presented by mouse fibroblasts.

Amidohydrolases↗
PubMed1990

Surprisingly uneven distribution of the T cell receptor V beta repertoire in wild mice.

We have examined TCR V beta expression in a collection of wild mice. Many of the mice were homozygous for a large deletion at the V beta locus, and many animals also suppressed expression of several V betas using self superantigens. Expression of V beta 8.2 was unexpectedly suppressed by a self superantigen in some wild mice, which was due to the presence in these animals of a variant V beta 8.2 gene. The amino acid changes in this gene product suggest contact sites between V beta and the superantigen. Although all V betas are expressed within each wild mouse population, individual mice have a limited and variable V beta repertoire. The independent origin of multiple V beta deletions and the presence of polymorphic self superantigens suggest that this variation may be maintained by balancing selection.

Amino Acid Sequence↗
PubMed1990

T cell tolerance.

The population of T cells which bears ab receptors is thought to be central to a successful immune response, since it is abbearing cells which stimulate B cells, which give rise to cytotoxic T cells and which secrete many of the essential lymphokines. Self tolerance in this population is therefore absolutely necessary and may even be sufficient to prevent autoimmunity. It is for this reason than immunologists have long tried to understand how tolerance is induced in these cells.

Animals↗