Sex-Specific T-Cell Regulation of Angiotensin II–Dependent Hypertension

Abstract

Studies suggest T cells modulate arterial pressure. Because robust sex differences exist in the immune system and in hypertension, we investigated sex differences in T-cell modulation of angiotensin II–induced increases in mean arterial pressure in male (M) and female (F) wild-type and recombination-activating-gene-1–deficient (Rag1 −/− ) mice. Sex differences in peak mean arterial pressure in wild-type were lost in Rag1 −/− mice (mm Hg: wild-type-F, 136±4.9 versus wild-type-M, 153±1.7; P <0.02; Rag1 −/− -F, 135±2.1 versus Rag1 −/− -M, 141±3.8). Peak mean arterial pressure was 13 mm Hg higher after adoptive transfer of male (CD3 M →Rag1 −/− -M) versus female (CD3 F →Rag1 −/− -M) T cells. CD3 M →Rag1 −/− -M mice exhibited higher splenic frequencies of proinflammatory interleukin-17A (2.4-fold) and tumor necrosis factor-α (2.2-fold)–producing T cells and lower plasma levels (13-fold) and renal mRNA expression (2.4-fold) of interleukin-10, whereas CD3 F →Rag1 −/− -M mice displayed a higher activation state in general and T-helper-1–biased renal inflammation. Greater T-cell infiltration into perivascular adipose tissue and kidney associated with increased pressor responses to angiotensin II if the T cell donor was male but not female and these sex differences in T-cell subset expansion and tissue infiltration were maintained for 7 to 8 weeks within the male host. Thus, the adaptive immune response and role of pro- and anti-inflammatory cytokine signaling in hypertension are distinct between the sexes and need to be understood to improve therapeutics for hypertension-associated disease in both men and women.