Enhanced Generation of Suppressor T Cells in Patients with Asthma Taking Oral Contraceptives

Abstract

Introduction. A dysregulation of regulatory T cells (Tregs) could play a major role in the pathogenesis of bronchial asthma. Sex-dependent differences as well as the impact of hormonal changes in the incidence and severity of asthma are widely recognized. Emerging evidence suggests that asthma symptoms are alleviated in female patients taking hormone oral contraceptives (OCs). The impact of OCs on the generation of induced Tregs (iTregs) was assessed in a cohort of female patients with asthma. Methods. Thirteen patients were included in this pilot study. During three distinct phases of their menstrual cycles, we measured exhaled nitric oxide (eNO) levels, forced expiratory volume at 1 second (FEV1s), asthma control test (ACT) score, sex steroid hormone levels in serum, natural Tregs in peripheral blood, and the ability of CD4⁺ T cells to generate iTregs ex vivo. Results. The luteal serum levels of estradiol and progesterone negatively correlated with the proportion of iTregs generated ex vivo in patients not taking OCs. In addition, physiological doses of estradiol and progesterone prevented the acquisition of a suppressor T cell phenotype in vitro. Interestingly, patients taking OCs had reduced serum sex hormone levels associated with higher iTreg induction, a better ACT score, and a tendency toward lower eNO levels. Conclusions. Our results identify an impact of sex hormones on the capacity of T cells to polarize towards a regulatory phenotype and suggest the regulation of peripheral T cell lineage plasticity as a potential mechanism underlying the beneficial effects of OCs in women with asthma.

• CD4 T cells
• estradiol
• induced regulatory T cells
• menstrual cycle
• progesterone

Acknowledgments

The authors thank Jennifer Strange and Greg Bauman from the University of Kentucky Flow Cytometry Service Facility for their assistance in collecting flow cytometry samples. For the statistical analysis, support was obtained from the Biostatistics, Epidemiology and Research Design (BERD) at the Center for Clinical and Translational Science (CCTS) and the Applied Statistics Laboratory (ASL) from the University of Kentucky.

Declaration of Interest Statement

A.C.V., M.C.R., G.I.E., A.M., T.G., M.K. and F.M. declare no financial or commercial conflict of interest. J.T. receives research funding from Merck and Dyax.

This work was performed at University of Kentucky, College of Medicine, Lexington, KY and supported by the National Center for Research Resources (NCRR), National Institutes of Health through Grant 2P20 RR020171 and by the NCRR and the National Center for Advancing Translational Sciences through Grant UL1TR000117 to F.M. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. J.T was the recipient of the Young Faculty Support Award, from The Foundation of the American College of Allergy, Asthma and Immunology.