HLA micropolymorphisms strongly affect peptide-MHC multimer-based monitoring of antigen-specific CD8+ T cell responses

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...

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Bibliographic Details
Published in:The Journal of immunology (1950) Vol. 192; no. 2; p. 641
Main Authors: van Buuren, Marit M, Dijkgraaf, Feline E, Linnemann, Carsten, Toebes, Mireille, Chang, Cynthia X L, Mok, Juk Yee, Nguyen, Melanie, van Esch, Wim J E, Kvistborg, Pia, Grotenbreg, Gijsbert M, Schumacher, Ton N M
Format: Journal Article
Language:English
Published: United States 15.01.2014
Subjects:
Alleles
Amino Acid Sequence
Antigens, Neoplasm - genetics
Antigens, Neoplasm - immunology
CD8-Positive T-Lymphocytes - immunology
Clone Cells - immunology
HLA-A2 Antigen - genetics
HLA-A2 Antigen - immunology
Humans
Lymphocytes, Tumor-Infiltrating - immunology
Lymphocytes, Tumor-Infiltrating - metabolism
Major Histocompatibility Complex - genetics
Major Histocompatibility Complex - immunology
Melanoma - genetics
Melanoma - immunology
Melanoma - metabolism
Molecular Sequence Data
Neoplasm Proteins - genetics
Neoplasm Proteins - immunology
Neoplasm Proteins - metabolism
Peptides - genetics
Peptides - immunology
Peptides - metabolism
Polymorphism, Genetic - genetics
Polymorphism, Genetic - immunology
Sequence Alignment
ISSN:1550-6606, 1550-6606
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Summary: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.
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ISSN:1550-6606
1550-6606
DOI:10.4049/jimmunol.1301770