We and others have shown an important role CD8+ cells in both experimental and human hypertension. CD8+ T cells are activated by antigens presented by major histocompatibility complex 1 (MHC1). C57BL/6 mice express two MHC1, referred to as H2-Kb and H2-Db. To identify antigenic peptides responsible for hypertension, we made two transgenic mice lacking the transmembrane domains of MHC1 and an added His-tag to the modified MHC1. These transgenes are driven by CD11c promoter, allowing expression in antigen presenting cells. The soluble Kb and Db (sKb and sDb) mice received 2 week infusions of sham or angiotensin II and their splenocytes placed in culture for two days. Ni-NTA beads were then used to bind the shed MHC-1 and these beads mixed with 10 6 T cells from other ang II infused mice (Figure panel A). CFSE dilution was used to monitor T cell proliferation. We found that sDb from ang II infused male mice, but not sham infused mice, potently stimulated proliferation of CD8+ T cells from ang II infused male mice. This degree of stimulation was significantly greater than that observed by sKb (Figure panel B). The shed MHC1 from female ang II-treated mice caused significantly less stimulation of female CD8+ T cells compared to male MHC1, in keeping with prior observations that female mice have less immune activation in hypertension. In summary, these data strongly suggest that unique antigens, presented in the context of H2-Db, are generated in hypertension. These data also suggest that there may be unique human lymphocyte antigens (HLAs), the analog of mouse MHC, that predispose to hypertension and related end-organ damage.