Oligoclonal CD8+ T Cells Play a Critical Role in the Development of Hypertension

Recent studies have emphasized a role of adaptive immunity, and particularly T cells, in the genesis of hypertension. We sought to determine the T-cell subtypes that contribute to hypertension and renal inflammation in angiotensin II-induced hypertension. Using T-cell receptor spectratyping to examine T-cell receptor usage, we demonstrated that CD8(+) cells, but not CD4(+) cells, in the kidney exhibited altered T-cell receptor transcript lengths in Vβ3, 8.1, and 17 families in response to angiotensin II-induced hypertension. Clonality was not observed in other organs. The hypertension caused by angiotensin II in CD4(-/-) and MHCII(-/-) mice was similar to that observed in wild-type mice, whereas CD8(-/-) mice and OT1xRAG-1(-/-) mice, which have only 1 T-cell receptor, exhibited a blunted hypertensive response to angiotensin II. Adoptive transfer of pan T cells and CD8(+) T cells but not CD4(+)/CD25(-) cells conferred hypertension to RAG-1(-/-) mice. In contrast, transfer of CD4(+)/CD25(+) cells to wild-type mice receiving angiotensin II decreased blood pressure. Mice treated with angiotensin II exhibited increased numbers of kidney CD4(+) and CD8(+) T cells. In response to a sodium/volume challenge, wild-type and CD4(-/-) mice infused with angiotensin II retained water and sodium, whereas CD8(-/-) mice did not. CD8(-/-) mice were also protected against angiotensin-induced endothelial dysfunction and vascular remodeling in the kidney. These data suggest that in the development of hypertension, an oligoclonal population of CD8(+) cells accumulates in the kidney and likely contributes to hypertension by contributing to sodium and volume retention and vascular rarefaction

Inhibition of Interleukin-17A, But Not Interleukin-17F, Signaling Lowers Blood Pressure, and Reduces End-Organ Inflammation in Angiotensin II–Induced Hypertension

Inflammatory cytokines play a major role in the pathophysiology of hypertension. The authors previously showed that genetic deletion of interleukin (IL)-17A results in blunted hypertension and reduced renal/vascular dysfunction. With the emergence of a new class of monoclonal antibody–based drugs for psoriasis and related autoimmune disorders that target IL-17 signaling, the authors sought to determine whether these antibodies could also reduce blood pressure, renal/vascular inflammation, and renal injury in a mouse model of hypertension. The authors show that antibodies to IL-17A or the IL-17RA receptor subunit, but not IL-17F, may be a novel adjunct treatment for hypertension and the associated end-organ dysfunction

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TIB Hannover: RN 5973(2106) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman

Critics role of IL-21 and T follicular helper cells in hypertension and vascular dysfunction

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 lg 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-gamma production. Tfh-like cells and GC B cells accumulated in the aorta, and plasma IgG1 was increased in hypertensive WT but not or 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