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.
Hypertension is the number one risk factor for cardiovascular and kidney disease throughout the world. The age of onset occurs later in women than men suggesting females are protected from the development of hypertension. Recent studies indicate that T cells (a group of white blood cells that play a central role in immunity) contribut to hypertension. We have discovered that a male T cell subset contributes to hypertension while a female T cell subset attenuates hypertension. Using a unique animal model, in which we can separate the effects of the sex chromosomes (XY vs XX) from the hormonal differences between males and females (e.g., testosterone vs estrogen), we propose to investigate the mechanisms by which female T cells protect males from hypertension. We expect this research to ultimately lead to novel therapeutic interventions for hypertensive disease in both men and women.
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