Discovery of post-translationally modified self-peptides that promote hypertension

Abstract

Post translational modifications can enhance immunogenicity of self-proteins. In several conditions including hypertension, systemic lupus, and heart failure, isolevuglandins (IsoLGs) are formed by lipid peroxidation and covalently bond with protein lysine residues. Here we show that the murine class-I major histocompatibility complex (MHC-I) variant H-2Db uniquely presents isoLG modified peptides and developed a computational pipeline that identifies structural features for MHC-I accommodation of such peptides. We identified isoLG-adducted peptides from renal proteins including the sodium glucose transporter 2, Cadherin 16, Kelch Domain containing protein 7A and solute carrier family 23, that are recognized by CD8+ T cells in tissues of hypertensive mice, induce T cell proliferation in vitro, and prime hypertension after adoptive transfer. Finally, we find similar patterns of isoLG-adducted antigen restriction in class-I human leukocyte antigens as in murine analogues. Thus, we have used a combined computational and experimental approach to define likely antigenic peptides in hypertension.