The adaptive immune system contributes to development of hypertension but the mechanisms or antigens involved are not known. Isoketals (IsoKs) are products of arachidonic acid oxidation that can cross-link lysine residues on proteins which in turn can be immunogenic. We sought to determine if IsoK-modified proteins serve as neoantigens presented by dendritic cells (DCs) to activate T cells in hypertension. Superoxide production by DCs was increased 5-fold by angiotensin II infusion compared to sham treated mice (334.0±49.7 versus 65.8±4.5 pmol/mg protein). This was NADPH-dependent as it did not occur in the gp91
phox-/-
mice. This increase in superoxide was associated with accumulation of IsoKs in DCs and activation of DC IL-6 production (1411.0±1330.2 versus 576.2±512.8 pg/ml). Treatment with a potent IsoK scavenger, 2-hydroxybenzylamine, markedly attenuated angiotensin II-induced hypertension (131.4 ± 9.4 mmHg versus 160.1 ± 5.1 mmHg in control mice). Finally we employed an immunization assay involving priming by adoptive transfer of DCs from either sham or angiotensin II-treated mice to naïve recipients. T cells from these recipients were then cultured for 10 days with DCs from either sham or angiotensin II treated mice. DCs from angiotensin II treated mice, but not sham mice, caused a striking activation of CD8
+
cells in this assay, as reflected by proliferation and polarization to Tc1 and Tc17 phenotypes. These studies show that angiotensin II-induced hypertension activates DCs, in large part by causing superoxide production and formation of IsoKs. We propose that IsoK-modified proteins can be presented as neoantigens by DCs, which in turn trigger T cell activation leading to hypertension.
DC isoketal-modified proteins activate T cells and promote hypertension