γδ T Cells Mediate Angiotensin II-Induced Hypertension and Vascular Injury
γδ T Cells Mediate Angiotensin II-Induced Hypertension and Vascular Injury
复制标题
DOI：
10.1161/circulationaha.116.027058
复制
发表时间：
2017-05-30
期刊：
影响因子：
37.8
通讯作者：
Schiffrin, Ernesto L.
中科院分区：
文献类型：
--
作者：
Caillon, Antoine;Mian, Muhammad Oneeb Rehman;Schiffrin, Ernesto L.
背景：先天性抗原提呈细胞和适应性免疫T细胞参与了高血压的发生发展。然而，T淋巴细胞亚群参与高血压的病理生理机制仍不清楚。表达γ δ T细胞受体（TCR）而不是α β TCR的一小部分先天性样T细胞可能在高血压免疫应答的启动中发挥作用。我们的目的是确定血管紧张素（Ang）II是否引起γ δ T细胞的动力学变化; γ δ T细胞缺乏是否减弱Ang II诱导的高血压、血管损伤和T细胞活化;以及γ δ T细胞是否与人类高血压相关。缺乏γ δ T细胞的雄性C57 BL/6野生型和Tcr δ（-/-）小鼠，或IP注射对照同种型IgG或γ δ T细胞耗竭抗体的野生型小鼠，血管紧张素II分别输注或不输注3天、7天或14天。流式细胞术测定T细胞分布，遥测收缩压（SBP），加压肌电图测定肠系膜动脉内皮功能。TCR δ恒定区基因表达水平和全血基因表达微阵列研究的临床数据，包括正常血压和高血压受试者，被用来证明γ δ T细胞和SBP.RESULTS之间的关联：7和14天的血管紧张素II输注增加野生型小鼠脾脏中γ δ T细胞的数量和活化（P< 0.05）。14天的Ang II输注增加了野生型小鼠的SBP（P< 0.01），降低了肠系膜动脉内皮功能（P< 0.01），而Tcr delta（-/-）小鼠的SBP和肠系膜动脉内皮功能均被消除（P< 0.01）。与同种型抗体处理的Ang II输注小鼠相比，抗TCR γ δ抗体诱导的γ δ T细胞耗竭减弱了Ang II诱导的SBP升高和内皮功能障碍（P< 0.05）。Ang Ⅱ诱导的Tcr δ（-/-）小鼠脾脏和血管周围脂肪组织T细胞活化减弱（P< 0.01）。在人类中，SBP和γ δ T细胞之间的关联通过整合全血TCR δ恒定区基因表达水平和年龄及性别的多元线性回归模型来证明（R-2= 0.12，P<1x 10（-6））。结论：γ δ T细胞介导小鼠中Ang II诱导的SBP升高、血管损伤和T细胞活化。γ δ T细胞可能有助于人类高血压的发展。
BACKGROUND: Innate antigen-presenting cells and adaptive immune T cells have been implicated in the development of hypertension. However, the T-lymphocyte subsets involved in the pathophysiology of hypertension remain unclear. A small subset of innate-like T cells expressing the gamma delta T cell receptor (TCR) rather than the alpha beta TCR could play a role in the initiation of the immune response in hypertension. We aimed to determine whether angiotensin (Ang) II caused kinetic changes in gamma delta T cells; deficiency in gamma delta T cells blunted Ang II-induced hypertension, vascular injury, and T-cell activation; and gamma delta T cells are associated with human hypertension.METHODS: Male C57BL/6 wild-type and Tcr delta(-/-) mice, which are devoid of gamma delta T cells, or wild-type mice injected IP with control isotype IgG or gamma delta T cell-depleting antibodies, were infused or not with Ang II for 3, 7, or 14 days. T-cell profiling was determined by flow cytometry, systolic blood pressure (SBP) by telemetry, and mesentery artery endothelial function by pressurized myography. TCR delta constant region gene expression levels and clinical data of a whole blood gene expression microarray study, including normotensive and hypertensive subjects, were used to demonstrate an association between gamma delta T cells and SBP.RESULTS: Seven-and 14-day Ang II infusion increased gamma delta T-cell numbers and activation in the spleen of wild-type mice (P< 0.05). Fourteen days of Ang II infusion increased SBP (P< 0.01) and decreased mesenteric artery endothelial function (P< 0.01) in wild-type mice, both of which were abrogated in Tcr delta(-/-) mice (P< 0.01). Anti-TCR gamma delta antibody-induced gamma delta T-cell depletion blunted Ang II-induced SBP rise and endothelial dysfunction (P< 0.05), compared with isotype antibody-treated Ang II-infused mice. Ang II-induced T-cell activation in the spleen and perivascular adipose tissue was blunted in Tcr delta(-/-) mice (P< 0.01). In humans, the association between SBP and gamma delta T cells was demonstrated by a multiple linear regression model integrating whole blood TCR delta constant region gene expression levels and age and sex (R-2= 0.12, P< 1x10(-6)).CONCLUSIONS: gamma delta T cells mediate Ang II-induced SBP elevation, vascular injury, and T-cell activation in mice. gamma delta T cells might contribute to the development of hypertension in humans.