Female spontaneously hypertensive rats (SHR) have more regulatory T cells (Tregs) in their kidneys than males. The goal of this study was to determine the impact of blood pressure (BP) on the renal immune profile. We hypothesize that increases in BP promote a pro-inflammatory renal T cell and cytokine profile in SHR, although females will have greater hormone-dependent increases in Tregs and males will have greater increases in Th17 cells. Renal T cell and cytokine profiles were assessed in male and female WKY and male and female SHR treated with vehicle or hydrochlorothiazide and reserpine from 6 to 12 (6-HCTZ) or 11 to 13 weeks of age (2-HCTZ). Regardless of sex, SHR had a more pro-inflammatory renal immune profile than WKY. 6-HCTZ attenuated age-related increases in BP and 2-HCTZ reversed hypertension compared to vehicle-treated SHR. Neither 6-HCTZ nor 2-HCTZ altered CD3+, CD4+, or CD8+ T cells in either sex. Both treatments decreased Tregs only in female SHR abolishing sex differences in Tregs. 6-HCTZ has no impact on Th17 cells in either sex and 2-HCTZ had a minimal impact on renal Th17 cells. To further assess mechanisms mediating sex differences in the renal immune profile, male and female SHR were gonadectomized to determine the impact of sex hormones. Gonadectomy increased pro-inflammatory markers in both sexes, suggesting that both male and female sex hormones are anti-inflammatory. In conclusion, BP contributes to sex differences in the renal T cell profile of SHR; female SHR increase renal Tregs in response to increases in BP.

T cells contribute to hypertension in male experimental models; data in females is lacking even though women are more likely to develop immune disorders. The goal of this study was to determine whether immune cells contribute to hypertension in female spontaneously hypertensive rats (SHR) and define the T cell profile in whole blood and kidneys of male and female SHR. We hypothesized that inflammatory cells contribute to hypertension in female SHR; however, male SHR have a higher blood pressure so we hypothesize they will have a heightened inflammatory profile. The lymphocyte inhibitor mycophenolate mofetil (MMF) was administered in a dose-dependent manner to SHR. At the highest dose (50 mg·kg(-1)·day(-1)), blood pressure was significantly decreased in both sexes, yet the percent decrease in blood pressure was greater in females (female: 12 ± 1%; males: 7 ± 1%, P = 0.01). Circulating and renal T cell profiles were defined using analytical flow cytometry. Female SHR had more circulating CD3(+), CD4(+), and pro-inflammatory CD3(+)CD4(+)RORγ(+) Th17 cells, whereas males had more immune-suppressive CD3(+)CD4(+)Foxp3(+) T regulatory cells. In the kidney, females had greater numbers of CD8(+) and T regulatory cells than males, whereas males had greater CD4(+) and Th17 cell infiltration. MMF decreased circulating and renal T cells in both sexes (P < 0.0001), although the effect of MMF on T cell subtypes was sex specific with females having greater sensitivity to MMF-induced decreases in lymphocytes. In conclusion, there is a lymphocyte contribution to the maintenance of hypertension in the female SHR and sex of the animal impacts the T cell profile.

Purpose Hypertension is a major risk factor for the development of cardiovascular disease, stroke and end-organ damage. There is a sex difference in blood pressure (BP) that begins in adolescence and continues into adulthood, where men have a higher prevalence of hypertension compared to women until the sixth decade of life. Less than 50% of hypertensive adults in the United States taking medication manage to control their BP to recommended levels using current therapeutic options, and women are more likely than men to have uncontrolled high BP. This is despite the fact that more women compared to men are aware that they have hypertension and women are more likely to seek treatment for the disease. Novel therapeutic targets need to be identified in both sexes to increase the percentage of hypertensive individuals with controlled BP. The purpose of this article is to review the available literature on the role of T cells in BP control in both sexes, and the potential therapeutic application/implications of targeting immune cells in hypertension. Methods A search of PUBMED was conducted to determine the impact of sex and gender on T cell-mediated control of BP. The search terms included sex, gender, estrogen, testosterone, inflammation, T cells, T regulatory cells, Th17 cells, hypertension and blood pressure. Additional data were included from our laboratory examining cytokine expression in the kidney of male and female SHR and differential genes expression in both the renal cortex and mesenteric arterial bed of male and female SHR. Findings There is a growing basic science literature regarding the role of T cells in the pathogenesis of hypertension and BP control, however, the majority of this literature has been performed exclusively in males despite the fact that both men and women develop hypertension. There is increasing evidence that while T cells also mediate BP in females, there are distinct differences in both the T cell profile and the functional impact of “male” vs. “female” T cells on cardiovascular health, although more work is needed to better define the relative impact of different T cell subtypes on BP in both sexes. Implications The challenge now is to fully understand the molecular mechanisms by which the immune system regulates BP and how the different components of the immune system interact so that specific mechanisms can be targeted therapeutically without compromising natural immune defenses.