• Blood pressure impacts the renal T cell profile of male and female spontaneously hypertensive rats

      Tipton, Ashlee J.; Department of Physiology (2014-03)
      Of the 68 million Americans with hypertension, fewer than 46% have their blood pressure (BP) adequately controlled and women are more likely than men to have uncontrolled hypertension. This underscores the critical need for new treatment options; however, this is a challenge due to our lack of knowledge regarding the mechanism(s) driving essential hypertension. T cells have been implicated in hypertension in males. Prior to our work, the role of T cells in hypertensive females had been unexplored. We demonstrate that female spontaneously hypertensive rats (SHR) have a decrease in BP in response to an immunosuppressant, supporting an immune component to their hypertension. We further defined a sex difference in the renal T cell and cytokine profile in SHR. Female SHR have a more anti-inflammatory immune profile in their kidneys than males. To gain insight into the mechanisms mediating sex differences in the immune profile, male and female SHR were gonadectomized. Gonadectomy increased pro-inflammatory markers in both sexes and attenuated anti-inflammatory markers particularly in females. Therefore, while both male and female sex hormones promote an anti-inflammatory immune profile, female ii sex hormones contribute greater to their more anti-inflammatory profile, but do not explain the sex difference. To determine the impact of hypertension on the renal immune profile, experiments measured renal T cells and cytokines in hypertensive male and female SHR, normotensive Wistar Kyoto rats (WKY), and SHR treated with antihypertensive therapy. All T cells and cytokines measured were higher in SHR compared to the same sex WKY. Moreover, antihypertensive therapy decreased renal Tregs only in female SHR. These data suggest that increased BP in both sexes is associated with an increase in renal inflammation; however female SHR have a compensatory increase in renal Tregs in response to increases in BP. TGF-β is a key cytokine regulating Treg and Th17 differentiation and we found that female SHR express more TGF-β than males. Experiments assessed if female SHR possessed a sex hormone or BP-mediated increase in renal TGF- β corresponding with increases in Tregs. We determined that loss of female sex hormones and increased BP in female SHR increase renal TGF-β expression. We conclude that BP status drive sex differences in the renal T cell and cytokine profile of SHR.
    • Indoleamine 2,3 -Dioxygenase Activity Suppresses T Cell Responses

      Johnson, Theodore S.; Department of Biochemistry and Molecular Biology (2002-06)
      Cells expressing indoleamine 2,3-dioxygenasc (IDO) inhibit proliferation of human T cells in vitro and protect murine fetuses from lethal attack by maternal T cells in vivo. This work investigates the hypothesis that IDO activity suppresses T cell responses. To test the prediction that pharmacological inhibition o f IDO enhances murine T cell responses in vivo, splenocytes from H-2Kb-specific T cell receptor transgenic (BM3) mice were injected into H-2Kb-expressing (CBK) recipients. As predicted, CD8+ T cell responses were augmented by 1-methyl-Dx-tryptophan (1-MeTrp) treatment o f recipient CBK mice, but only when BM3 donor T cells were derived from male mice. To further evaluate the prediction that IDO-expressing antigen presenting cells (APCs) inhibit antigen-specific T cell responses, we prepared IDO- and vectortransfected murine tumor cells expressing H-2Kb. BM3 T cell proliferation was diminished in co-cultures with IDO-transfected MCS7G cells, relative to vcctortransfected MCS7G cells. Furthermore, IDO-transfected MCS7G cells failed to prime H-2b-specific recall responses in allogeneic CBA mice unless co-administered with 1-MeTrp or endotoxin adjuvant. These results show that IDO-expressing APCs inhibit murine T cell responses in vitro and in vivo, and demonstrate the efficacy o f 1-MeTrp treatment in reversing the effects o f murine IDO-mediated T cell suppression in vivo.