Abstract 074: Discovery Of Post-Translationally Modified Self-peptides Responsible For T-cell Autoimmunity In Hypertension

Abstract

Introduction: Isolevuglandins (isoLGs) are lipid peroxidation products that covalently bond lysine residues, forming self-antigens that drive T cell inflammation in hypertension. We created a library of isoLG-adducted self-antigens and tested their ability to activate T cells and induce hypertension. Methods and Results: Using the Rosetta protein modeling software we developed a computational pipeline estimating isoLG-modified peptide binding for class I major histocompatilibty complex (MHC-I), creating a screening library of peptide candidates. We pulsed dendritic cells (DCs) with candidate peptides before co-culture with T cells from hypertensive mice stained with CFSE cell tracker dye (Fig 1A). Conjugating an MHC-I probe with candidate peptides showed 11 isoLG adducted peptides were recognized by CD8 + T cells in the aortas of hypertensive mice (Fig 1B), of which 6 also caused T cell proliferation (Fig 1C-D). We adoptively transferred DCs pulsed with these 6 peptides before treatment with a sub-pressor dose of angiotensin II. 4 of the isoLG-adducted peptides induced hypertension in vivo , while unadducted peptides did not (Fig 1E). Conclusion: Our work identifies specific self-peptides that, when modified by isoLG, cause T cell activation and hypertension.