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K Snoke

Publications and source records attributed to K Snoke.

10 recordsLinked to original sources
PubMed1996

Antigen analogs as tools to study T-cell activation function and activation.

Herein we review data relating to the molecular mechanism of T-cell receptor antagonists, their effect on thymic education, the occurrence of naturally occurring antigen analogs, and the therapeutic potential of the TCR antagonist approach. Our data suggest that MHC bound antigen analogs which antagonize the mature T-cell response, bind the T-cell receptor below a crucial affinity threshold required to stimulate the early biochemical events necessary for activation, such as phosphatidylinositol metabolism and the Ca2+ influx. The same peptides do not inhibit the formation of APC/T-cell complexes, suggesting interference with more complex equilibria such as receptor oligomerization and co-receptor interaction. Our laboratory and others have also begun to investigate how these antigen analogs may affect the processes involved in thymic education. Non-stimulatory antagonist peptides can elicit deletion of CD4+/CD8+ thymocytes suggesting a lower affinity requirement for negative selection than for activation. These data also demonstrate that these antigen analogs can, indeed, act upon immature T cells. We have also reviewed evidence that antagonists may, in fact, occur in nature. Recent data suggest that viral mutations resulting in altered immunodominant epitopes may produce antagonist determinants potentially involved in immunosuppression and viral persistence. Finally, we discuss the therapeutic potential of antigen analogs and TCR antagonism in autoimmune disease and allergy.

Animals↗
PubMed1994

Negative selection of CD4+ CD8+ thymocytes by T-cell receptor peptide antagonists.

Antigen-induced activation of T cells can be specifically inhibited by antigen analogs that have been termed T-cell receptor peptide antagonists. These antagonists appear to act by inducing the formation of nonstimulatory or partially stimulatory complexes between T-cell receptors and the major histocompatibility complex molecules presenting the peptides. Herein, we have investigated the effect of T-cell receptor peptide antagonists on thymocyte negative selection. First, peptide antagonists were identified for the cytochrome c-specific T-cell clone AD10. These peptides were then tested for their ability to induce negative selection in an in vitro model system using thymocytes from mice transgenic for the AD10 T-cell receptor. Though unable to induce mature T-cell activation, the T-cell receptor peptide antagonists induced deletion of CD4+ CD8+ thymocytes. These results suggest that negative selection of CD4+ CD8+ thymocytes can be induced by T-cell receptor interactions of a lower affinity than those required for mature T-cell activation.

Animals↗
PubMed1994

Development of high potency universal DR-restricted helper epitopes by modification of high affinity DR-blocking peptides.

Pan DR-binding peptides engineered by introducing anchor residues for different DR motifs within a polyalanine backbone bound 10 of 10 DR molecules tested, with affinities, in most cases, in the nanomolar range. Because of the small methyl group exposed for T cell recognition, these peptides were poor immunogens but effective blockers of DR-restricted antigen presentation. Introduction of bulky and charged residues at positions accessible for T cell recognition yielded extremely powerful Pan DR epitope peptides (PADRE). These peptides elicited powerful responses in vitro from human peripheral blood mononuclear cells (PBMC). Because these cells also cross-react on certain mouse class II alleles, we could also demonstrate that PADRE peptides are active in vivo. In one example of their capacity to elicit T help, they were approximately 1000 times more powerful than natural T cell epitopes. We propose that PADRE peptides may be useful in the development of subunit vaccines.

Alleles↗
PubMed1994

TCR antagonism and T cell tolerance can be independently induced in a DR-restricted, hemagglutinin-specific T cell clone.

The outcome of TCR engagement with peptide-MHC is of central importance for the immune response of the host. TCR antagonism is one phenomenon known which is characterized by selective inhibition of T cell responses by non-stimulatory antigen analogs. T cell anergy is another state resulting in T cell unresponsiveness, generally characterized by lack of proliferation and lymphokine production. In the present study, the relationship between TCR antagonism and T cell anergy was examined by using protocols known to induce either phenomenon. Re-isolation experiments demonstrated that antagonized T cells were not tolerized, in that they were fully capable of responding to a subsequent antigen challenge. Conversely, while high doses of soluble antigen could efficiently induce T cell tolerance, TCR antagonists, either alone or in conjunction with suboptimal antigen doses, could not. Taken together, these data demonstrate that TCR antagonism and T cell tolerance are phenomena independent of each other.

Antigen-Presenting Cells↗
PubMed1994

Antigen analogs/MHC complexes as specific T cell receptor antagonists.

Recent studies demonstrated that antigen analogs can act as powerful and specific inhibitors of T cell activation, leading to the formulation of the concept that antigen analog/MHC complexes may act as antagonists of the T cell receptor (TCR). TCR antagonism appears to be associated with engagement of the TCR below a crucial affinity threshold necessary for full T cell activation. Studies addressing the molecular mechanism of this effect suggest that TCR antagonists could act by interfering with membrane-related events (such as proper receptor clustering) that might precede intracellular signaling. Discovery of the TCR antagonism phenomenon also suggested a possible rational approach to antigen-specific immunointervention in allergies and autoimmune diseases. The feasibility of such an approach is now being actively investigated. Finally, TCR antagonist peptides may provide a useful tool to probe TCR-peptide/MHC interactions involved in the process of thymic education.

Animals↗
PubMed1993

The inhibition of different T cell lines specific for the same antigen with TCR antagonist peptides.

To further understand and evaluate the phenomenon of TCR antagonism, we wished to determine whether analogs of an antigenic determinant could antagonize a specific polyclonal response. To this end, the ability of TCR antagonist peptides to inhibit a panel of five different DR4w4-restricted, influenza hemagglutinin 307-319-specific T cell lines was examined. An analysis of their V beta and J beta usage indicated that each of these five T cell lines expressed different TCR. A series of HA 307-319 single amino acid substituted analogs were used to determine the fine Ag specificities of the different lines. Ag analogs that demonstrated little or no stimulatory capacity were then examined for their ability to act as TCR antagonists by inhibiting the proliferative response of these five lines. Overall, 17 different peptide analogs capable of antagonizing at least one T cell line were identified. Although no single analog was capable of inhibiting all five T cell lines, two different analogs were identified that were capable of inhibiting four of five of the T cell specificities examined.

Amino Acid Sequence↗
PubMed1993

Effect of T-cell receptor antagonism on interaction between T cells and antigen-presenting cells and on T-cell signaling events.

T-cell receptor (TCR) antagonism induced by complexes of antigen analogue with major histocompatibility complex (MHC) molecules results in efficient inhibition of antigen-dependent T-cell responses. We have investigated some of the possible mechanisms by which TCR antagonists bound to the MHC molecules of antigen-presenting cells (APCs) can inhibit T-cell activation. Using a nonstimulatory analogue of the antigenic peptide influenza hemagglutinin-(307-319), we showed that MHC/antagonist complexes completely inhibit very early intracellular events of antigen-dependent T-cell activation, such as inositol phosphate turnover and Ca2+ influx. In a parallel series of experiments, the effect of TCR antagonist peptide on membrane-related activation events was also investigated. It was found that MHC/antagonist complexes on the surface of APCs did not induce stable conjugates with T cells and, most interestingly, did not inhibit antigen-induced conjugate formation. Thus, our data suggest that antagonistic peptides do not interfere with the cellular events that are required for stable T-cell/APC conjugate formation but do inhibit early biochemical events required for T-cell proliferation. The data are discussed with respect to the role of surface receptor clustering in TCR antagonism.

Animals↗
PubMed1993

Functional consequences of engagement of the T cell receptor by low affinity ligands.

The mechanisms involved in TCR antagonism by Ag analog/MHC have been analyzed. A detailed structure-activity relationship study indicated that modification of any of the major T cell contact residues of the peptide molecule can yield a powerful antagonist. It was also shown that as the analog structure increased in similarity to the Ag, the capacity to antagonize Ag-TCR interaction increased up to the point that the analogs themselves became antigenic. These data strongly suggest an affinity-related mechanism whereby a certain affinity is required for signaling through the TCR, and that below this level there can be sufficient affinity to engage the receptor such that triggering does not occur and antagonism can be detected. Taking advantage of this information, antagonist peptides active down to the 10 nM range were engineered. Thus, this approach demonstrates for the first time a rational approach to designing effective, selective low m.w. compounds with high potential in treatment of allergies and autoimmune diseases.

Amino Acids↗
PubMedDate not supplied

Antigen analogues as antagonists of the T cell receptor.

Complexes of antigen analogues and major histocompatibility complexes have been demonstrated to function as effective antagonists of the T cell receptor (TCR). It was observed that modification of any of the major T cell contact residues can create powerful TCR antagonists. Increasing similarity of antagonist to antigen structure resulted in increased capacity to act as a TCR antagonist up to a point beyond which the analogues themselves showed antigenicity. These data strongly suggested that peptide: TCR interaction with a certain low affinity may still be sufficient for engagement of the receptor but not for signalling, thus resulting in antagonism. It was found that the presentation of antagonistic peptides alone did not induce the formation of stable conjugates between antigen presenting cells and T cells, but rather that presentation of antigen was required to induce the initial interaction of APC with T cells in cell:cell conjugates. This antigen-dependent conjugate formation was not affected by the antagonist, while very early intracellular biochemical events such as PI turnover and CA2+ flux were inhibited.

Antigen-Presenting Cells↗