T and B cells have been implicated in hypertension, but the mechanisms by which they produce a coordinated response is unknown. T follicular helper (Tfh) cells that produce interleukin 21 (IL21) promote germinal center (GC) B cell responses leading to immunoglobulin (Ig) production. Here we investigate the role of IL21 and Tfh cells in hypertension. In response to angiotensin (Ang) II-induced hypertension, T cell IL21 production is increased, and Il21-/- mice develop blunted hypertension, attenuated vascular end-organ damage, and decreased interleukin 17A (IL17A) and interferon gamma production. Tfh-like cells and GC B cells accumulate in the aorta and plasma IgG1 is increased in hypertensive WT but not Il21-/-mice. Furthermore, Tfh cell deficient mice develop blunted hypertension and vascular hypertrophy in response to Ang II infusion. Importantly, IL21 neutralization reduces blood pressure (BP) and reverses endothelial dysfunction and vascular inflammation. Moreover, recombinant IL21 impairs endothelium-dependent relaxation ex vivo and decreases nitric oxide production from cultured endothelial cells. Finally, we show in humans that peripheral blood T cell production of IL21 correlates with systolic BP and IL17A production. These data suggest that IL21 may be a novel therapeutic target for the treatment of hypertension and its micro- and macrovascular complications.
Bethany L. Dale, Arvind K. Pandey, Yuhan Chen, Charles D. Smart, Fanny Laroumanie, Mingfang Ao, Liang Xiao, Anna E. Dikalova, Sergey I. Dikalov, Fernando Elijovich, Jason D. Foss, Natalia R. Barbaro, Justin P. Van Beusecum, Serpil M. Deger, Aseel Alsouqi, Hana A. Itani, Allison E. Norlander, Matthew R. Alexander, Shilin Zhao, T. Alp Ikizler, Holly M. Scott Algood, Meena S. Madhur