The role of dendritic cell-mediated T cell activation in hypertension

Duke University, Durham NC

Investigators

Abstract

PROJECT ABSTRACT Hypertension affects roughly 30% of the U.S. population and is a significant risk factor for cardiovascular and kidney disease. Insufficient reduction of blood pressure in many hypertensive patients highlights a need for the development of novel treatment options. In recent years, studies have implicated the adaptive immune system, particularly T lymphocytes, in the development and maintenance of persistent hypertension. Activated T lymphocytes infiltrate the kidneys during the progression of hypertension and mediate elevations in pressure by promoting sodium retention and/or inducing renal and vascular injury. Activation of T cells occurs via interaction with antigen presenting cells, of which dendritic cells (DC) are the most potent. Dendritic cells sample antigens in peripheral tissues and present antigen-derived peptides to T cells in secondary lymphoid organs, allowing naïve T cells to clonally divide upon recognition of these peptides. T cells subsequently travel to the affected tissue and contribute to a specific inflammatory response. In the setting of hypertension, the mechanisms of T cell activation and the putative antigens that induce a specific T cell response are unknown. We hypothesize that dendritic cells mediate sodium retention and blood pressure elevation by activating pro- hypertensive T lymphocytes. We will utilize a murine model lacking DCs (Flt3-/-, or DC KO) and a murine model with spontaneous DC activation (CD11c Cre+ A20flox/wt, or DC ACT) to elucidate mechanisms through which DCs contribute to hypertension. Preliminary data show that DC KO mice have blunted hypertension, whereas DC ACT mice have augmented hypertension, validating both an essential role for DCs in the pathogenesis of hypertension and the relevance of our models in understanding the relationship between blood pressure regulation and DC function. Further understanding of the immunologic mechanisms underlying blood pressure regulation will direct the development of novel therapies for hypertension.