Variation in cytotoxic T-lymphocyte responses to peptides derived from tyrosinase-related protein-2

Myers, Cheryl; Dionne, Sara O.; Shakalya, Kishore; Mahadevan, Daruka; Smith, Margaret H.; Lake, Douglas F.

doi:10.1016/j.humimm.2007.11.010

Cited by 2 publications

(1 citation statement)

References 31 publications

(28 reference statements)

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“…These effects can be observed if the side chain is at the interface of the MHC helices and the TCR, or if its interaction with a pocket of the MHC alters the entire backbone conformation of the peptide (Gardiner et al, 2007; Myers et al, 2008; Racape et al, 2006; Rohren et al, 1994; Slansky et al, 2000). Accordingly, these changes may improve binding to the MHC while also reducing the binding of the TCR.…”

Section: Introductionmentioning

confidence: 99%

Engineering the binding properties of the T cell receptor:peptide:MHC ternary complex that governs T cell activity

Bowerman

Crofts

Chlewicki

et al. 2009

Molecular Immunology

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The potency of a T cell is determined in large part by two interactions, binding of a cognate peptide to the MHC, and binding of the T cell receptor (TCR) to this pepMHC. Various studies have attempted to assess the relative importance of these interactions, and to correlate the corresponding binding parameters with the level of T cell activity mediated by the peptide. To further examine the properties that govern optimal T cell activity, here we engineered both the peptide:MHC interaction and the TCR:pepMHC interaction to generate improved T cell activity. Using a system involving the 2C TCR and its allogeneic pepMHC ligand, QL9-Ld, we show that a peptide substitution of QL9 (F5R), increased the affinity and stability of the pep-Ld complex (e.g. cell surface t½ values of 13 minutes for QL9-Ld versus 87 minutes for F5R-Ld). However, activity of peptide F5R for 2C T cells was not enhanced because the 2C TCR bound with very low affinity to F5R-Ld compared to QL9-Ld (KD = 300 μM and KD = 1.6 μM, respectively). To improve the affinity, yeast display of the 2C TCR was used to engineer two mutant TCRs that exhibited higher affinity for F5R-Ld (KD = 1.2 and 6.3 μM). T cells that expressed these higher affinity TCRs were stimulated by F5R-Ld in the absence of CD8, and the highest affinity TCR exhibited enhanced activity for F5R compared to QL9. The results provide a guide to designing the explicit binding parameters that govern optimal T cell activities.

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Section: Introductionmentioning

confidence: 99%

Engineering the binding properties of the T cell receptor:peptide:MHC ternary complex that governs T cell activity

Bowerman

Crofts

Chlewicki

et al. 2009

Molecular Immunology

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CTL recognition of a novel HLA-A*0201-binding peptide derived from glioblastoma multiforme tumor cells

Myers

Hanavan

Antwi

et al. 2011

Cancer Immunol Immunother

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Genetic instability of tumor cells can result in translation of proteins that are out of frame, resulting in expression of neopeptides. These neopeptides are not self-proteins and therefore should be immunogenic. By eluting peptides from human glioblastoma multiforme (GBM) tumor cell surfaces and subjecting them to tandem mass spectrometry, we identified a novel peptide (KLWGLTPKVTPS) corresponding to a frameshift in the 3' beta-hydroxysteroid dehydrogenase type 7 (HSD3B7) gene. HLA-binding algorithms predicted that a 9-amino acid sequence embedded in this peptide would bind to HLA-A*0201. We confirmed this prediction using an HLA-A*0201 refolding assay followed by live cell relative affinity assays, but also showed that the 12-mer binds to HLA-A*0201. Based on the 9-mer sequence, optimized peptide ligands (OPL) were designed and tested for their affinities to HLA-A*0201 and their abilities to elicit anti-peptide and CTL capable of killing GBM in vitro. Wild-type peptides as well as OPL induced anti-peptide CTL as measured by IFN-γ ELISPOTS. These CTL also killed GBM tumor cells in chromium-51 release assays. This study reports a new CTL target in GBM and further substantiates the concept that rational design and testing of multiple peptides for the same T-cell epitope elicits a broader response among different individuals than single peptide immunization.

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Variation in cytotoxic T-lymphocyte responses to peptides derived from tyrosinase-related protein-2

Cited by 2 publications

References 31 publications

Engineering the binding properties of the T cell receptor:peptide:MHC ternary complex that governs T cell activity

Engineering the binding properties of the T cell receptor:peptide:MHC ternary complex that governs T cell activity

CTL recognition of a novel HLA-A*0201-binding peptide derived from glioblastoma multiforme tumor cells

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