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: Marit M van Buuren, Feline E Dijkgraaf, Carsten Linnemann, Mireille Toebes, Cynthia X L Chang, Juk Yee Mok, Melanie Nguyen, Wim J E van Esch, Pia Kvistborg, Gijsbert M Grotenbreg, Ton N M Schumacher
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 192 Issue 2 Pg. 641-8 (Jan 15 2014) ISSN: 1550-6606 [Electronic] United States
• PMID: 24342804 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Neoplasm
• HLA-A2 Antigen
• Neoplasm Proteins
• Peptides

Topics

• Alleles
• Amino Acid Sequence
• Antigens, Neoplasm (genetics, immunology)
• CD8-Positive T-Lymphocytes (immunology)
• Clone Cells (immunology)
• HLA-A2 Antigen (genetics, immunology)
• Humans
• Lymphocytes, Tumor-Infiltrating (immunology, metabolism)
• Major Histocompatibility Complex (genetics, immunology)
• Melanoma (genetics, immunology, metabolism)
• Molecular Sequence Data
• Neoplasm Proteins (genetics, immunology, metabolism)
• Peptides (genetics, immunology, metabolism)
• Polymorphism, Genetic (genetics, immunology)
• Sequence Alignment