Response by Caillon et al to Letter Regarding Article, “γδ T Cells Mediate Angiotensin II-Induced Hypertension and Vascular Injury”
Authors: Antoine Caillon, Ku-Geng Huo, Pierre Paradis, Ernesto L. Schiffrin
Journal: Circulation (2017)

In Response:Campbell raises the concern regarding our study on γδ T cells and hypertension 1 that the dose (490 ng•kg -1 •min -1 ) and subcutaneous route of angiotensin II infusion is too high in comparison with that required to increase blood pressure intravenously. 2 There are indeed important differences in bioavailability between both routes of administration.The dose of 490 ng•kg -1 •min -1 induces similar pressor responses and plasma levels in rats as intravenous angiotensin II at 20 ng•kg -1 •min -1 , according to Dr Campbell's own review from a few years ago. 2 He points out that high concentrations of angiotensin II delivered into the subcutaneous tissue may activate a variety of cells expressing angiotensin receptors, including T cells, but this occurs with larger doses of angiotensin II of 1000 and 2000 ng•kg -1 •min -1 infused subcutaneously.It is unknown whether this occurs at the dose we used.Dr Campbell also brings up the possibility that subcutaneous and intravenous models of angiotensin II-induced hypertension provide different information. 2However, conclusions about this are limited by the lack of direct comparison between the 2 modes of administration in the same species and in the same laboratory.We selected the angiotensin II 490 ng•kg -1 •min -1 subcutaneous infusion model of hypertension because it was used by us previously, 3 and by many other investigators, to study the role of the immune system in hypertension, of which we cite only 2, 4,5 which allows our results to be compared with those of other studies.Thus, we believe that the criticism whether γδ T cells participate in the mediation of angiotensin II-induced blood pressure elevation, vascular injury, and T-cell activation in mice in our study is unwarranted.Dr Campbell suggests caution interpreting the correlation between blood pressure and blood T-cell receptor γ constant region (TRGC) gene expression in the cohort of patients that we examined, which included hypertensive subjects in both groups of coronary artery disease (CAD) and non-CAD cases, because we did not adjust for antihypertensive medication in any of our statistical models.However, adjusting for angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, β-adrenergic receptor blockers, calcium channel blockers, and diuretics did not significantly change the partial correlation analyses corrected for age, sex, and CAD.When we generated a new multiple linear regression model combining all 4 TRGC1/2 probe sets, age, sex, and CAD, and angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, β-adrenergic receptor blockers, calcium blockers, and diuretics (R 2 =0.17), a likelihood ratio test showed no significant difference between this new model and the model that includes TRGC1/2 probe sets, age, sex, and CAD (R 2 =0.13).However, other confounders that could include measured and unmeasured parameters may still account, in part, for the observed correlations between blood pressure and whole blood TRGC gene expression in this patient cohort.This represents a limitation of the study, but does not change the conclusion that our data in humans together with the data in mice strongly suggest that γδ