HLA-B27, but not HLA-B7, immunodominance to influenza is ERAP dependent.
Endoplasmic reticulum-associated aminopeptidase-1 (ERAP1) plays a critical role in the processing of peptides prior to binding to MHC class I molecules. In this article, we show for the first time, to our knowledge, that the HLA-B27 immunodominant influenza nucleoprotein (NP) 383-391 epitope is made as an N-terminally extended 14-mer before it is trimmed by ERAP. In the absence of ERAP, there is a significant reduction in the CTL response to the B27/NP383-391 epitope in influenza A (flu)-infected B27/ERAP(-/-) mice. With the use of tetramer staining, the number of naive CD8(+) T cells expressing TCR Vβ8.1 in B27/ERAP(-/-) transgenic mice is significantly lower than that seen in B27/ERAP(+/+) mice. HLA-B27 surface expression in naive and flu-infected B27/ERAP(-/-) mice is also lower than the expression seen for the same allele in naive and flu-infected B27/ERAP(+/+) mice. In contrast, surface expression of HLA-B7 was unaffected by the absence of ERAP in B7/ERAP(-/-) transgenic mice. The B7-restricted NP418-426 CTL response in flu-infected B7/ERAP(-/-) and B7/ERAP(+/+) mice was also similar. These results provide, to our knowledge, the first in vivo demonstration of ERAP functionally influencing host immune response in an HLA allele-specific manner. This principle has relevance to diseases such as ankylosing spondylitis, in which HLA-B27 and ERAP jointly contribute to disease predisposition.
Division of Genetics & Development, Toronto Western Research Institute, Toronto, Ontario, Canada M5T-2S8; Institute of Medical Sciences, University of Toronto Faculty of Medicine, Toronto, Ontario, Canada M5S 1A8; Department of Immunology, University of Toronto, Toronto, Ontario, Canada M5S 1A8; and.
Ali
A
Akram
Division of Genetics & Development, Toronto Western Research Institute, Toronto, Ontario, Canada M5T-2S8;
Aifeng
A
Lin
Division of Genetics & Development, Toronto Western Research Institute, Toronto, Ontario, Canada M5T-2S8; Institute of Medical Sciences, University of Toronto Faculty of Medicine, Toronto, Ontario, Canada M5S 1A8; Department of Immunology, University of Toronto, Toronto, Ontario, Canada M5S 1A8; and.
Eric
E
Gracey
University of Toronto, Department of Laboratory Medicine and Pathobiology. Division of Pathology, St. Michael's Hospital, Toronto, Ontario, Canada M5B 1W8.
Catherine J
CJ
Streutker
Division of Genetics & Development, Toronto Western Research Institute, Toronto, Ontario, Canada M5T-2S8; Institute of Medical Sciences, University of Toronto Faculty of Medicine, Toronto, Ontario, Canada M5S 1A8; Department of Immunology, University of Toronto, Toronto, Ontario, Canada M5S 1A8; and robert.inman@uhn.ca.
Robert D
RD
Inman
D000483:Alleles; D000626:Aminopeptidases / Q000235:genetics / Q000276:immunology*; D000818:Animals; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D020022:Genetic Predisposition to Disease; D015796:HLA-B27 Antigen / Q000235:genetics / Q000276:immunology*; D015793:HLA-B7 Antigen / Q000235:genetics / Q000276:immunology*; D006801:Humans; D053122:Influenza A Virus, H3N2 Subtype / Q000235:genetics / Q000276:immunology*; D051379:Mice; D009976:Orthomyxoviridae Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D013167:Spondylitis, Ankylosing / Q000235:genetics / Q000276:immunology / Q000473:pathology
D015796:HLA-B27 Antigen; D015793:HLA-B7 Antigen; D000626:Aminopeptidases