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 IL-21 promote germinal center (GC) B cell responses, leading to Ig production. Here we investigate the role of IL-21 and Tfh cells in hypertension. In response to angiotensin II–induced (Ang II–induced) hypertension, T cell IL-21 production was increased, and Il21–/– mice developed blunted hypertension, attenuated vascular end-organ damage, and decreased IL-17A and IFN-γ production. Tfh-like cells and GC B cells accumulated in the aorta, and plasma IgG1 was increased in hypertensive WT but not Il21–/– mice. Furthermore, Tfh cell–deficient mice developed blunted hypertension and vascular hypertrophy in response to Ang II infusion. Importantly, IL-21 neutralization reduced BP and reversed endothelial dysfunction and vascular inflammation. Moreover, recombinant IL-21 impaired endothelium-dependent relaxation ex vivo and decreased NO production from cultured endothelial cells. Finally, we show in humans that peripheral blood T cell production of IL-21 correlated with systolic BP and IL-17A production. These data suggest that IL-21 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
Hypertension is associated with increased CD4+ T cell production of IL-21, and IL-21 deficiency blunts the hypertensive response to Ang II infusion.