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

In experimental hypertension and humans with hypertension, T cells with an effector phenotype infiltrate target tissues like the kidney and vasculature and release cytokines including IL-17A and IFNγ, which in turn cause tissue damage and dysfunction. A major mechanism for T cell activation in hypertension and related disorders is the accumulation of highly reactive electrophiles called isolevuglandins, or IsoLGs. IsoLGs are formed by peroxidation of arachidonic acid and covalently bond with lysine residues in proteins. Peptides derived from IsoLG-adducted proteins are presented by antigen-presenting cells, where they are recognized as foreign immunogens by subsets of T cells. Self-peptides that serve as substrates for IsoLG-modification have not yet been identified. In this work, we demonstrate that IsoLG-adducted peptides are restricted to the class-I major histocompatibility complex (MHC-I) variant H-2Db in mice. We developed a computational screening pipeline that identified key features necessary for MHC-I to accommodate IsoLG-adducted peptides and produced candidate epitopes for screening. After synthesizing candidate peptides, we identify IsoLG-adducted peptides that are recognized by CD8+ T cells in target tissues of hypertensive mice, induce T cell proliferation in vitro, and cause hypertension after adoptive transfer. Finally, we find similar patterns of IsoLG-adducted antigen restriction occur between class-I human leukocyte antigens as in murine analogues. Thus, we have identified specific self-peptides that can mediate T cell activation and hypertension. This discovery holds significant implications for understanding and treating hypertension and hypertension-related illnesses. ### Competing Interest Statement The authors have declared no competing interest.