Mice expressing human ERAP1 variants associated with ankylosing spondylitis have altered T-cell repertoires and NK cell functions as well as increased in utero and perinatal mortality

摘要

Specific variants of endoplasmic reticulum-associated aminopeptidase 1 (ERAP1) identified by genome-wide association study modify the risk for developing ankylosing spondylitis. We previously confirmed that disease-associated ERAP1 variants have altered enzymatic abilities that can impact upon the production of pro-inflammatory cytokines from cells expressing the same ERAP1 variants. To determine if these ERAP1 variants also impacted immune responses in vivo, we generated two strains of transgenic mice expressing human ERAP1 genes containing non-synonymous single-nucleotide polymorphisms associated with an increased (ERAP1-High) or decreased (ERAP1-Low) risk for developing autoimmune disease. After vaccination with foreign antigens, ERAP1-High mice generated unique populations of antigen-specific T-cell clones. The expression of ERAP1-High also reduced MHC-I expression on the surface of multiple cell types, demonstrating a global impact on the MHC-I peptidome. ERAP1 variants also affected the innate immune system, because NK cells from murine ERAP1 (mERAP1) knockout mice and ERAP1-High/mERAP1^−/− mice had decreased surface expression of the activating receptor NKG2D on their NK and T cells, and NK cells derived from mERAP1^−/− mice or ERAP1-Low mice demonstrated more active NK cell killing than NK cells derived from wild-type or ERAP1-High mice. Finally, these studies were conducted in female mice, as all male ERAP1-High mice died in utero or shortly after birth, making ERAP1-High one of the only dominant lethal autosomal genes known in mammals. Together, these results present the first direct evidence that human disease-associated ERAP1 variants can greatly alter survival, as well as antigen presentation, T-cell repertoire and NK cell responses in vivo.