Role of Dendritic Cell-mediated T Cell Activation in Salt-sensitive Hypertension

Duke University, Durham NC

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Abstract

? DESCRIPTION (provided by applicant): Hypertension impacts 1 billion people worldwide leading to catastrophic cardiovascular complications. Recent studies indicate that activated T lymphocytes make a key contribution to hypertension in part by stimulating sodium retention in the kidney. T lymphocytes undergo activation when the T cell receptor (TCR) binds a cognate antigen on the surface of an antigen presenting cell (APC). Our preliminary studies indicate that dendritic cells, the most potent APC lineage, infiltrate the kidney and activate T cells during the course of hypertension. After collecting and processing antigens, dendritic cells encounter and activate T cells in the lymph nodes draining the kidney with consequent downregulation of CD62L and upregulation of CD44 on these T cells. Expression of CCR7 on the T cell allows its entry into the lymph node for this critical dendritic cell encounter, and we find that mice deficiet of CCR7 (CCR7 KO) have a blunted chronic hypertensive response. We therefore hypothesize that dendritic cells potentiate blood pressure elevation by stimulating CCR7+ T lymphocytes to enhance sodium reabsorption in the kidney. To test this possibility we will induce hypertension in mice in which dendritic cells are conditionally ablated (DC DTR), genetically deficient (DC KO), or spontaneously activated (DC ACT). Our experiments will use two hypertension models that depend on T cell-driven sodium retention, the deoxycorticosterone acetate (DOCA)-salt and low dose chronic angiotensin (Ang) II infusion models. The DOCA-salt model mimicks hypertension in human patients with elevated aldosterone activity whereas the Ang II infusion model is relevant to the large numbers of human patients that respond to inhibition of the renin angiotensin system. Our preliminary data using radiotelemetry blood pressure measurements reveal that DC KO mice and DC ACT mice have blunted and augmented hypertensive responses, respectively, to low dose (300ng/kg/min) Ang II without measurable renal damage. To monitor specific TCR activation in the DC KO mice in vivo during hypertension, we have crossed the DC KOs with a GFP reporter strain in which T cells fluoresce green following TCR engagement by the APC. To determine whether the augmented hypertension seen in the DC ACT mice depends on DC-mediated T cell activation, we have crossed our DC ACT mice with Rag1-deficient mice lacking functional T cells. In CCR7-deficient (KO) mice and controls, we will further examine DOCA-salt or Ang II-induced blood pressure elevation, renal sodium retention, and dendritic cell-mediated activation of T lymphocytes in the kidney's draining lymph node. To determine whether CCR7 expression on the T cell, the DC, or both is required to mount a full hypertensive response, we will induce hypertension in CCR7 KO recipients of wild-type (WT) or CCR7 KO bone marrow, T cells, or DCs. Elucidating the mechanisms through which dendritic cells regulate T cell-dependent blood pressure elevation should aid the design of potent, immune-directed therapies for the prevention and treatment of hypertension.