Immune Modulation of Hypertension

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DESCRIPTION (provided by applicant): Recent studies indicate that T cells can modulate arterial pressure. We found that adoptive transfer of male but not female CD3+, CD4+ and CD8+ T cells can mediate Ang II-dependent hypertension in male Rag1 deficient mice. These observations indicate sex specific ations of T cells determine resistance and vulnerability in the regulation of hypertension by the immune system. In aim 1, we will determine if T cell-mediated susceptibility and resistance to hypertension induced by Ang II infusion in the male Rag1-/- host is due to gonad-dependent or gonad-independent effects of the sex chromosomes (XX vs XY) on the T cell donor and how these effects link to end organ damage and T cell responses. In aim 2, we will determine if sex-specific T cell subset responses to Ang II infusion in the male Rag1-/- host are due to sex differences in T cell angiotensin type 1 and type 2 receptors (AT1R and AT2R) and how these receptor- mediated T cell effects link to blood pressure, end organ damage and T cell function. Aim 3 will determine the role of pro- and anti-inflammatory cytokines in CD4+ and CD8+- mediated susceptibility and resistance to Ang II-induced hypertension and link these findings to end organ damage. Defining the mechanisms by which T cell sub- specification and T cell function are regulated by sex in a model of Ang II-dependent hypertension may provide an explanation for the delayed onset of hypertension in premenopausal women compared with age-matched men. Furthermore, discovering immune regulatory phenotypes associated with resistance and susceptibility to hypertension induced by Ang II could uncover T cell subset specific targets and strategies for treating hypertension in both sexes.