Innate Lymphoid Cells Mediate Hypertension In T Cell Deficient Hosts

T cells have been shown to contribute to hypertension, however, hypertension occurs in settings of T cell deficiency, such as human immunodeficiency virus infection and following chemotherapy. We studied two colonies of RAG-1 -/- mice with disparate responses to angiotensin II (Ang II) infusion. Ang II increased both systolic and diastolic pressure in RAG-1 -/- mice from Jackson labs (RAG-1 -/-US ) but had no effect in a colony of RAG-1 -/- mice housed at our Pozzilli facility (RAG-1 -/-POZ ) for the past 14 years (SBPs 169 ± 2 vs 114 ± 3 mmHg, p < 0.003). While both lacked T and B cells, the RAG-1 -/-US mice exhibited a striking expansion of natural killer and both type 1 and type 3 innate lymphoid cells, while the RAG-1 -/-POZ mice did not. In RAG-1 -/-US mice, NK cells and ILC1s produced IFNγ, while ILC3s produced IL-17A. Immunoclearing of IL-17A, but not IFNγ prevented the hypertension in RAG-1 -/-US mice. There were differences in global gene expression and DNA methylation status in NK1.1 + /NKp46 + cells between these two colonies and notably β2-AdR and IL-10 expression was significantly lower in RAG-1 -/-US mice. Knockdown of the β2-AdR using intra-splenic infusion of siRNA in RAG-1 -/-POZ mice led to a hypertensive response resembling that observed in wild type and RAG-1 -/-US mice. We also found striking differences in DNA methylation patterns in innate lymphoid cells of RAG-1 -/-US vs RAG-1 -/-POZ mice and treatment with the DNA methyltransferase inhibitor 5-azacytidine prevented hypertension in RAG-1 -/-US mice. Single cell sequencing showed that 5-azacytidine also reduced splenic populations of NK and ILC3 cells and reduced the presence of the transcription factor RORγt, which defines ILC3s. Ang II infusion caused only a transient elevation of blood pressure in NSG/MHCI/II -/- mice that lack T cells and innate lymphoid cells but led to sustained hypertension following adoptive transfer of either T cells or NK1.1 + /NKp46 + cells to these animals. We conclude that DNA methylation likely modulates expansion of NK and innate lymphoid cells. Either T cells or innate lymphoid cells can contribute to hypertension, and the latter can compensate by serving as a source of cytokines like IL-17A when T cells are deficient.