title: HLA micropolymorphisms strongly affect peptide-MHC multimer-based monitoring of antigen-specific CD8+ T cell responses.
abstract: Peptide-MHC (pMHC) multimers have become one of the most widely used tools to measure Ag-specific T cell responses in humans. With the aim of understanding the requirements for pMHC-based personalized immunomonitoring, in which individuals expressing subtypes of the commonly studied HLA alleles are encountered, we assessed how the ability to detect Ag-specific T cells for a given peptide is affected by micropolymorphic differences between HLA subtypes. First, analysis of a set of 10 HLA-A*02:01-restricted T cell clones demonstrated that staining with pMHC multimers of seven distinct subtypes of the HLA-A*02 allele group was highly variable and not predicted by sequence homology. Second, to analyze the effect of minor sequence variation in a clinical setting, we screened tumor-infiltrating lymphocytes of an HLA-A*02:06 melanoma patient with either subtype-matched or HLA-A*02:01 multimers loaded with 145 different melanoma-associated Ags. This revealed that of the four HLA-A*02:06-restricted melanoma-associated T cell responses observed in this patient, two responses were underestimated and one was overlooked when using subtype-mismatched pMHC multimer collections. To our knowledge, these data provide the first demonstration of the strong effect of minor sequence variation on pMHC-based personalized immunomonitoring, and they provide tools to prevent this issue for common variants within the HLA-A*02 allele group.
authors.affiliation: Division of Immunology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands;
authors.forename: Marit M
authors.initials: MM
authors.lastname: van Buuren
authors.forename: Feline E
authors.initials: FE
authors.lastname: Dijkgraaf
authors.forename: Carsten
authors.initials: C
authors.lastname: Linnemann
authors.forename: Mireille
authors.initials: M
authors.lastname: Toebes
authors.forename: Cynthia X L
authors.initials: CX
authors.lastname: Chang
authors.forename: Juk Yee
authors.initials: JY
authors.lastname: Mok
authors.forename: Melanie
authors.initials: M
authors.lastname: Nguyen
authors.forename: Wim J E
authors.initials: WJ
authors.lastname: van Esch
authors.forename: Pia
authors.initials: P
authors.lastname: Kvistborg
authors.forename: Gijsbert M
authors.initials: GM
authors.lastname: Grotenbreg
authors.forename: Ton N M
authors.initials: TN
authors.lastname: Schumacher
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002999:Clone Cells / Q000276:immunology; D015789:HLA-A2 Antigen / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism; D008285:Major Histocompatibility Complex / Q000235:genetics / Q000276:immunology*; D008545:Melanoma / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D010455:Peptides / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011110:Polymorphism, Genetic / Q000235:genetics* / Q000276:immunology; D016415:Sequence Alignment
chemical_list: D000951:Antigens, Neoplasm; D015789:HLA-A2 Antigen; D009363:Neoplasm Proteins; D010455:Peptides