Qualitative and Quantitative Differences in T Cell Receptor Binding of Agonist and Antagonist Ligands

In the present study, the relation between the efficacy of immunotherapy, and the strength and site of T cell activation during immunotherapy was evaluated. We used a model of allergic asthma in which OVA-sensitized and OVA-challenged mice display increased airway hyperresponsiveness, airway inflammation, and Th2 cytokine production by OVA-specific T cells. In this model, different immunotherapy strategies, including different routes of administration, or treatment with entire OVA or the immunodominant T cell epitope OVA323–339, or treatment with a peptide analogue of OVA323–339 with altered T cell activation capacity were studied. To gain more insight in how immunotherapy affects allergen-specific T cells, the site of Ag-specific T cell activation and the magnitude of the T cell response induced during different immunotherapy strategies were determined using an adoptive transfer model. Our data suggest that amelioration of airway hyperresponsiveness and inflammation is associated with the induction of a strong, synchronized, and systemic T cell response, resulting in a decreased OVA-specific Th2 response. In contrast, deterioration of the disease after immunotherapy is associated with the induction of a weak nonsynchronized T cell response, resulting in the enhancement of the OVA-specific Th2 response after challenge.

Section: Discussionmentioning

confidence: 99%

The Efficacy of Immunotherapy in an Experimental Murine Model of Allergic Asthma Is Related to the Strength and Site of T Cell Activation During Immunotherapy

Janssen

Oosterhout

Nijkamp

et al. 2000

“…Protocols to identify high avidity T cells would provide an opportunity to analyze in ex vivo assays the interclonal T cell competition during T cell expansion and to sort high avidity T cell clones to be used in adoptive T cell transfer therapy (6). Several factors can influence the avidity of interactions between TCR and MHC class I/peptide complexes, including the density and stability of TCR/ MHC class I peptide complexes (7)(8)(9), the colocalization of TCR and CD8 in the immune synapse (7, 10 -13), and the binding of CD8 molecules (14). Initial reports suggested that the intensity of staining by tetrameric soluble MHC/peptide complexes (tetramers) could be used as a parameter to identify high avidity T cells (15)(16)(17)(18), and more recently it has been shown that stability of tetramer binding to T cell clones could be used to assess the affinity of TCR recognition (19,20).…”

mentioning

confidence: 99%

High Avidity Antigen-Specific CTL Identified by CD8-Independent Tetramer Staining

Choi

Chen

Wooldridge

et al. 2003

Tetrameric MHC/peptide complexes are important tools for enumerating, phenotyping, and rapidly cloning Ag-specific T cells. It remains however unclear whether they can reliably distinguish between high and low avidity T cell clones. In this report, tetramers with mutated CD8 binding site selectively stain higher avidity human and murine CTL capable of recognizing physiological levels of Ag. Furthermore, we demonstrate that CD8 binding significantly enhances the avidity as well as the stability of interactions between CTL and cognate tetramers. The use of CD8-null tetramers to identify high avidity CTL provides a tool to compare vaccination strategies for their ability to enhance the frequency of high avidity CTL. Using this technique, we show that DNA priming and vaccinia boosting of HHD A2 transgenic mice fail to selectively expand large numbers of high avidity NY-ESO-1157–165-specific CTL, possibly due to the large amounts of antigenic peptide delivered by the vaccinia virus. Furthermore, development of a protocol for rapid identification of high avidity human and murine T cells using tetramers with impaired CD8 binding provides an opportunity not only to monitor expansion of high avidity T cell responses ex vivo, but also to sort high avidity CTL clones for adoptive T cell transfer therapy.

“…While neither partial agonists nor null peptides interfere with the signaling promoted by the full agonist, antagonist peptides are able to inhibit TCR activation induced by the agonist peptide. Biochemical studies have recently correlated the dissociation rate (k off ) of the TCR-MHC/peptide interaction with the biological activity of APLs (13)(14)(15)(16)(17)(18). Thus, while partial agonists dissociate faster from the TCR than the full agonists, antagonist peptides have even faster dissociation rates than partial agonists.…”

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confidence: 99%

Altered Peptide Ligand-Mediated TCR Antagonism Can Be Modulated by a Change in a Single Amino Acid Residue Within the CDR3β of an MHC Class I-Restricted TCR

Kalergis

Nathenson

2000

The Ag receptor of cytotoxic CD8+ T lymphocytes recognizes peptides of 8–10 aa bound to MHC class I molecules. This Ag recognition event leads to the activation of the CD8+ lymphocyte and subsequent lysis of the target cell. Altered peptide ligands are analogues derived from the original antigenic peptide that commonly carry amino acid substitutions at TCR contact residues. TCR engagement by these altered peptide ligands usually impairs normal T cell function. Some of these altered peptide ligands (antagonists) are able to specifically antagonize and inhibit T cell activation induced by the wild-type antigenic peptide. Despite significant advances made in understanding TCR antagonism, the molecular interactions between the TCR and the MHC/peptide complex responsible for the inhibitory activity of antagonist peptides remain elusive. To approach this question, we have identified altered peptide ligands derived from the vesicular stomatitis virus peptide (RGYVYQGL) that specifically antagonize an H-2Kb/vesicular stomatitis virus-specific TCR. Furthermore, by site-directed mutagenesis, we altered single amino acid residues of the complementarity-determining region 3 of the β-chain of this TCR and tested the effect of these point mutations on Ag recognition and TCR antagonism. Here we show that a single amino acid change on the TCR CDR3β loop can modulate the TCR-antagonistic properties of an altered peptide ligand. Our results highlight the role of the TCR complementarity-determining region 3 loops for controlling the nature of the T cell response to TCR/altered peptide ligand interactions, including those leading to TCR antagonism.