title: Changes to peptide structure, not concentration, contribute to expansion of the lowest avidity cytotoxic T lymphocytes.
abstract: The efficient in vitro expansion of antigen-specific CD8+ cytotoxic T lymphocytes (CTL) for use in adoptive immunotherapy represents an important clinical goal. Furthermore, the avidity of expanded CTL populations often correlates closely with clinical outcome. In our study, high-avidity CTL lines could be expanded ex vivo from an antigen-primed animal using low peptide concentration, and intermediate peptide concentrations favored the generation of lower avidity CTL. Further increases in peptide concentration during culture inhibited the expansion of all peptide-specific CD8+ cells. In contrast, a single amino acid variant peptide efficiently generated functional CTL populations at high or low peptide concentration, which responded to wild-type epitope with the lowest average avidity seen in this study. We propose that for some peptides, the efficient generation of low-avidity CTL responses will be favored by stimulation with altered peptide rather than high concentrations of wild-type epitope. In addition, some variant peptides designed to have improved binding to major histocompatibility complex class I may reduce rather than enhance the functional avidity for the wild-type peptide of ex vivo-expanded CTL. These observations are relevant to in vitro expansion of CTL for immunotherapy and strategies to elicit regulatory or therapeutic immunity to neo-self-antigen when central tolerance has eliminated high-avidity, cognate T cells.
authors.affiliation: Centre for Immunology and Cancer Research, University of Queensland, Princess Alexandra Hospital, Brisbane, Australia. gleggatt@cicr.uq.edu.au
authors.forename: Graham R
authors.initials: GR
authors.lastname: Leggatt
authors.forename: Sharmal
authors.initials: S
authors.lastname: Narayan
authors.forename: Germain J P
authors.initials: GJ
authors.lastname: Fernando
authors.forename: Ian H
authors.initials: IH
authors.lastname: Frazer
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002470:Cell Survival / Q000276:immunology; D022801:Complementarity Determining Regions / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D004797:Enzyme-Linked Immunosorbent Assay; D019674:Genes, T-Cell Receptor beta / Q000502:physiology; D006801:Humans; D007114:Immunization; D007371:Interferon-gamma / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009856:Oncogene Proteins, Viral / Q000276:immunology / Q000378:metabolism; D050725:Papillomavirus E7 Proteins; D010446:Peptide Fragments / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D022801:Complementarity Determining Regions; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D010446:Peptide Fragments; C059731:oncogene protein E7, Human papillomavirus type 16; D007371:Interferon-gamma