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

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

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

In this study, we developed three optimized peptide ligands (OPL) that demonstrate increased affinities for HLA-A*0201 compared with wild-type tyrosinase-related protein-2 (TRP-2) peptide. The OPL contain amino acids from TRP-2(180-188) and preferred primary and auxiliary HLA-A*0201 anchor residues. Cytotoxic T lymphocyte (CTL) lines were generated against wild-type TRP-2 peptide and OPL by multiple rounds of peptide stimulation of peripheral blood mononuclear cells from HLA-A2*0201+ healthy individuals. CTL reactivity profiles to three different OPL were donor-dependent. Among donors, at least one OPL was particularly stimulatory and elicited high levels of CTL that cross-reacted with wild-type TRP-2 peptide. Cytotoxicity assays using CTL raised on wild-type TRP-2 peptide or OPL demonstrated lysis of HLA-A2-positive glioblastoma cells. Molecular models of TRP-2 and OPL peptides docked with HLA-A*0201 demonstrated that substitution of F for S at position 1 (P1) oriented the peptides favoring a pi-pi aromatic interaction with W 167 of HLA-A*0201. This in turn positions P5 and P8 aromatic rings to face solvent that may promote binding to the T-cell receptor, leading to a robust T-cell activation. The results of this study further substantiate the concept that rational design and testing of multiple peptides for the same T-cell epitope should elicit a broader response among different individuals than single peptide immunization. Our results may partially explain why some patients have better clinical responses to peptide-based immunotherapy, whereas others respond poorly.

Original languageEnglish (US)
Pages (from-to)24-31
Number of pages8
JournalHuman Immunology
Volume69
Issue number1
DOIs
StatePublished - Jan 1 2008

Keywords

  • Cytotoxic T lymphocytes (CTL)
  • Human leukocyte antigen (HLA)
  • Optimized peptide ligand (OPL)
  • Tyrosinase related protein-2 (TRP-2)

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Fingerprint Dive into the research topics of 'Variation in cytotoxic T-lymphocyte responses to peptides derived from tyrosinase-related protein-2'. Together they form a unique fingerprint.

  • Cite this