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

Abstract

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 (TCR) spectratyping to examine TCR usage we demonstrated that CD8+ cells, but not CD4+ cells, in the kidney exhibited altered TCR 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 WT mice, while CD8−/− mice and OT1xRAG-1−/− mice, which have only one TCR, 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 accumulate in the kidney and likely contribute to hypertension by contributing to sodium and volume retention and vascular rarefaction.

Immune Mechanisms in Arterial Hypertension

“…This in turn could promote sodium and volume retention. 73 It should be recognized that mice lacking CD4 + cells also lack Tregs and this perhaps predisposes these animals to worsened hypertension.…”

T cell senescence and cardiovascular diseases

“…Indeed, it has been recently reported that oligoclonal CD8 ? T cells play a crucial role in the development of hypertension in a mouse model [83]. In addition, a recent study has identified oxidatively modified proteins by highly reactive c-ketoaldehydes (isoketals) as CD8 ?…”

Renal Transporter Activation During Angiotensin-II Hypertension is Blunted in Interferon-γ −/− and Interleukin-17A −/− Mice

“…1-3 Mice and rats lacking T-lymphocytes exhibit blunted hypertensive responses to experimental hypertension, restored by adoptive transfer of T-cells. 4-6 Trott et al recently provided evidence that a population of CD8 + T-cells, not CD4 + T-cells, play a critical role in the development Ang II infusion hypertension. 6 Recent evidence also indicates that isoketal-modified proteins are formed in dendritic cells, and that these are recognized as non-self and promote T cell activation.…”

“…4-6 Trott et al recently provided evidence that a population of CD8 + T-cells, not CD4 + T-cells, play a critical role in the development Ang II infusion hypertension. 6 Recent evidence also indicates that isoketal-modified proteins are formed in dendritic cells, and that these are recognized as non-self and promote T cell activation. 7 In the kidney, cytokines released from these cells activate local production of angiotensin II (AngII), even when systemic levels of AngII are low.…”