MassIVE MSV000089312

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The Behcet's disease risk variant HLA-B51/ ERAP1-Hap10 alters human CD8 T cell immunity

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Description

The ERAP1 haplotype Hap10 encodes for a variant allotype of the ER-resident peptide-trimming aminopeptidase ERAP1 with low enzymatic activity resembling functional KO. This haplotype recessively confers the highest risk for Behcet's diseases (BD) currently known, but only in carriers of HLA-B*51, the classical risk factor for the disease. The mechanistic implications and biological consequences of this epistatic relationship are unknown. Here, we aimed to determine its biological relevance and functional impact, including its effect on the HLA-class I peptidome. We generated CRISPR-Cas9 ERAP1 KOs from HLA-B51+ LCL and analyzed the HLA I-bound peptidome for peptide length differences. ERAP1 KO cells showed peptidomes with longer peptides above 9mer than WT LCL (which carried heterozygous ERAP1 Hap7/Hap2 encoding for an allotype with medium-high trimming activity), pointing to a disproportionately large number of under-trimmed peptides. Such under-trimmed peptides may alter immunogenicity likely through a change in immunodominance of the ensuing CD8 T cell response signifying the potential relevance of this finding to disease risk and adaptive immune responses in human ERAP1 Hap10/ HLA-B*51 carriers with and without BD. For a more detailed discussion, immunogenicity and immune-phenotype data, please see the related manuscript: Cavers et al. The Behcet's disease risk variant HLA-B51/ ERAP1-Hap10 alters human CD8 T cell immunity. [doi:10.25345/C5QN5ZG0B] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: peptidome ; HLA ; Behcet's disease ; ERAP1

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Principal Investigators:
(in alphabetical order) 		Beatrix Ueberheide, New York Grossman School of Medicine, USA
Submitting User: Trixi
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