Human ERAP2 polymorphisms elicit differentiated antigen processing in response to virus

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Presentation Time: 09:45 AM - 10:00 AM
Abstract ID: 6063 - B

Presenting Author:
J David Peske , Assistant Professor at Johns Hopkins Univ. Sch. of Med.

Abstract:

Balancing selection maintains functional genetic diversity enabling populations to adapt to diverse environments; it can also increase disease risk in certain individuals. Endoplasmic reticulum aminopeptidase 2 (ERAP2), an enzyme involved in antigen processing, has two divergent haplogroups maintained by balancing selection and associated with immune-mediated diseases. The ERAP2-B haplogroup protects against autoimmune disease and encodes an efficiently degraded transcript in myeloid cells at rest but an alternative isoform, ERAP2_Iso3, in response to influenza infection. Here, we report that the ERAP2 haplogroups arose in humans with individuals of African ancestry exhibiting additional genetic ERAP2-B diversity. We identified that nucleic acid sensing induces expression of ERAP2_Iso3 in MDMs. This is controlled by a an intronic cis-regulatory element consisting of two copies of a tandem repeat and a SNP. The truncated ERAP2_Iso3 protein alters peptide processing specificity and stimulates CD8 T cell responses in transgenic mice. These findings establish that genetic variation at the ERAP2 locus encodes a protein in response to virus that causes differentiated antigen processing shaping the peptide-MHC targets of T cell responses. More broadly, our study offers a compelling example of how an ancient and prevalent disease-associated genetic variation in humans interacts with common environmental exposures to generate distinct and diverse cellular responses.