γδ T Cells Mediate Angiotensin II-Induced Hypertension and Vascular Injury.
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 γδ T cell receptor (TCR) rather than the αβ 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 γδ T cells; deficiency in γδ T cells blunted Ang II-induced hypertension, vascular injury, and T-cell activation; and γδ T cells are associated with human hypertension.


METHODS
Male C57BL/6 wild-type andTcrδ-/-mice, which are devoid of γδ T cells, or wild-type mice injected IP with control isotype IgG or γδ 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 γ 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 γδ T cells and SBP.


RESULTS
Seven- and 14-day Ang II infusion increased γδ 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 inTcrδ-/-mice (P<0.01). Anti-TCRγδ antibody-induced γδ 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 inTcrδ-/-mice (P<0.01). In humans, the association between SBP and γδ T cells was demonstrated by a multiple linear regression model integrating whole blood TCR γ constant region gene expression levels and age and sex (R2=0.12,P<1×10-6).


CONCLUSIONS
γδ T cells mediate Ang II-induced SBP elevation, vascular injury, and T-cell activation in mice. γδ T cells might contribute to the development of hypertension in humans.
From Lady Davis Institute for Medical Research (A.C., M.O.R.M., J.C.F.-A., K.-G.H., T.B., S.O., P.P., E.L.S.), Department of Medicine, Sir Mortimer B. Davis-Jewish General Hospital (E.L.S.), McGill University, Montréal, Québec, Canada; and Universitaire Ziekenhuizen Leuven Gasthuisberg, University of Leuven, Belgium (P.R.S.).
Antoine
A
Caillon
From Lady Davis Institute for Medical Research (A.C., M.O.R.M., J.C.F.-A., K.-G.H., T.B., S.O., P.P., E.L.S.), Department of Medicine, Sir Mortimer B. Davis-Jewish General Hospital (E.L.S.), McGill University, Montréal, Québec, Canada; and Universitaire Ziekenhuizen Leuven Gasthuisberg, University of Leuven, Belgium (P.R.S.).
Muhammad Oneeb Rehman
MOR
Mian
From Lady Davis Institute for Medical Research (A.C., M.O.R.M., J.C.F.-A., K.-G.H., T.B., S.O., P.P., E.L.S.), Department of Medicine, Sir Mortimer B. Davis-Jewish General Hospital (E.L.S.), McGill University, Montréal, Québec, Canada; and Universitaire Ziekenhuizen Leuven Gasthuisberg, University of Leuven, Belgium (P.R.S.).
Julio C
JC
Fraulob-Aquino
From Lady Davis Institute for Medical Research (A.C., M.O.R.M., J.C.F.-A., K.-G.H., T.B., S.O., P.P., E.L.S.), Department of Medicine, Sir Mortimer B. Davis-Jewish General Hospital (E.L.S.), McGill University, Montréal, Québec, Canada; and Universitaire Ziekenhuizen Leuven Gasthuisberg, University of Leuven, Belgium (P.R.S.).
Ku-Geng
KG
Huo
From Lady Davis Institute for Medical Research (A.C., M.O.R.M., J.C.F.-A., K.-G.H., T.B., S.O., P.P., E.L.S.), Department of Medicine, Sir Mortimer B. Davis-Jewish General Hospital (E.L.S.), McGill University, Montréal, Québec, Canada; and Universitaire Ziekenhuizen Leuven Gasthuisberg, University of Leuven, Belgium (P.R.S.).
Tlili
T
Barhoumi
From Lady Davis Institute for Medical Research (A.C., M.O.R.M., J.C.F.-A., K.-G.H., T.B., S.O., P.P., E.L.S.), Department of Medicine, Sir Mortimer B. Davis-Jewish General Hospital (E.L.S.), McGill University, Montréal, Québec, Canada; and Universitaire Ziekenhuizen Leuven Gasthuisberg, University of Leuven, Belgium (P.R.S.).
Sofiane
S
Ouerd
From Lady Davis Institute for Medical Research (A.C., M.O.R.M., J.C.F.-A., K.-G.H., T.B., S.O., P.P., E.L.S.), Department of Medicine, Sir Mortimer B. Davis-Jewish General Hospital (E.L.S.), McGill University, Montréal, Québec, Canada; and Universitaire Ziekenhuizen Leuven Gasthuisberg, University of Leuven, Belgium (P.R.S.).
Peter R
PR
Sinnaeve
From Lady Davis Institute for Medical Research (A.C., M.O.R.M., J.C.F.-A., K.-G.H., T.B., S.O., P.P., E.L.S.), Department of Medicine, Sir Mortimer B. Davis-Jewish General Hospital (E.L.S.), McGill University, Montréal, Québec, Canada; and Universitaire Ziekenhuizen Leuven Gasthuisberg, University of Leuven, Belgium (P.R.S.).
Pierre
P
Paradis
From Lady Davis Institute for Medical Research (A.C., M.O.R.M., J.C.F.-A., K.-G.H., T.B., S.O., P.P., E.L.S.), Department of Medicine, Sir Mortimer B. Davis-Jewish General Hospital (E.L.S.), McGill University, Montréal, Québec, Canada; and Universitaire Ziekenhuizen Leuven Gasthuisberg, University of Leuven, Belgium (P.R.S.). ernesto.schiffrin@mcgill.ca.
Ernesto L
EL
Schiffrin
D000804:Angiotensin II / Q000633:toxicity*; D000818:Animals; D006801:Humans; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000172:deficiency*; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D057772:Vascular System Injuries / Q000139:chemically induced / Q000378:metabolism*
D016692:Receptors, Antigen, T-Cell, gamma-delta; D000804:Angiotensin II
angiotensin II; blood pressure; immune system; vascular biology; γδ T cells