From the Division of Nephrology, Department of Medicine, Durham VA and Duke University Medical Center, NC (Y.W., N.P.R., J.Z., X.L., J.R., R.G., S.D.C.).
Departments of Anesthesiology (J.R.P.), Duke University Medical Center, Durham, NC.
Hypertension. 2020 Mar;75(3):869-876. doi: 10.1161/HYPERTENSIONAHA.119.14148. Epub 2020 Jan 27.
Activated T lymphocytes that infiltrate blood pressure control organs make a critical contribution to the pathogenesis of hypertension. Dendritic cells act as potent antigen-presenting cells to stimulate prohypertensive T cells. However, the mechanisms that facilitate the recruitment of prohypertensive T cells and dendritic cells into the kidney's draining lymph node during hypertension require elucidation. As CCR7 (C-C motif chemokine receptor type 7) directs the homing of lymphocytes and dendritic cells into lymph nodes, we posited that dendritic cell-mediated T lymphocyte stimulation in the renal lymph node is CCR7 dependent and required for a full hypertensive response. We found that CCR7-deficient (CCR7 KO) mice had a blunted hypertensive response in our model of chronic Ang II (angiotensin II) infusion. Ang II-infused CCR7 KO animals had exaggerated accumulation of CD8 T cells in the kidney but reduced numbers of CD4 and CD8 T cells in the kidney's draining lymph node. To understand whether CCR7-dependent homing of T lymphocytes or dendritic cells into the lymph node regulates the hypertensive response, we injected CCR7 KO or wild-type T cells or dendritic cells into CCR7 KO recipients, neither of which restored the full hypertensive response to Ang II infusion. However, adoptive transfer of wild-type but not CCR7 KO T lymphocytes into RAG1 (recombination-activating gene 1)-deficient mice that lack a lymphocyte niche restored full blood pressure elevation during Ang II infusion. Thus, CCR7-dependent interactions between T lymphocytes and dendritic cells are essential for T lymphocyte stimulation and hypertension accruing from inappropriate activation of the renin-angiotensin system.
浸润血压控制器官的活化 T 淋巴细胞对高血压的发病机制有重要贡献。树突状细胞作为有效的抗原呈递细胞，刺激致高血压 T 细胞。然而，在高血压期间，促进致高血压 T 细胞和树突状细胞进入肾脏引流淋巴结的机制仍需阐明。由于 CCR7（C 型趋化因子受体 7）指导淋巴细胞和树突状细胞进入淋巴结，我们假设树突状细胞介导的 T 淋巴细胞刺激在肾淋巴结中是 CCR7 依赖性的，并且是完全高血压反应所必需的。我们发现，在我们的慢性 Ang II（血管紧张素 II）输注模型中，CCR7 缺陷（CCR7 KO）小鼠的高血压反应减弱。Ang II 输注的 CCR7 KO 动物在肾脏中 CD8 T 细胞的积累明显增加，但肾脏引流淋巴结中 CD4 和 CD8 T 细胞的数量减少。为了了解 CCR7 依赖性 T 淋巴细胞或树突状细胞归巢到淋巴结是否调节高血压反应，我们将 CCR7 KO 或野生型 T 细胞或树突状细胞注入 CCR7 KO 受体中，两者均不能恢复 Ang II 输注引起的完全高血压反应。然而，将野生型而非 CCR7 KO T 淋巴细胞过继转移到缺乏淋巴细胞龛的 RAG1（重组激活基因 1）缺陷小鼠中，可恢复 Ang II 输注期间的完全血压升高。因此，T 淋巴细胞和树突状细胞之间 CCR7 依赖性相互作用对于 T 淋巴细胞刺激和由于肾素-血管紧张素系统的不当激活而导致的高血压累积至关重要。
