Role of Estrogen receptor signaling in the activation and differentiation of human CD4+ T cells
MALARD A. 1,2, POLANSKY J. 1,2,3
1 International Max Planck Research School for Infectious Diseases and Immunology, Berlin, Germany; 2 BIH Center for Regenerative Therapies (BCRT), Berlin, Germany; 3 Deutsches Rheuma-Forschungszentrum Berlin, Berlin, Germany
Immune responses are generally more robust in females, leading to a higher protection against infectious diseases, but also an increased prevalence of most autoimmune conditions. Paradoxically, the female hormone 17-β-estradiol (E2) has been shown to inhibit the differentiation of healthy mouse naïve CD4+ T cells (Tn) into Th17 cells, which promote inflammation in many autoimmune conditions, including systemic lupus erythematosus (SLE). Our aim is to better understand the effect of E2 on human CD4+ T cells, with a particular focus on Th17 cell differentiation.
We measured the effect of E2 on healthy human blood-derived CD4+ Tn cell proliferation and activation in in vitro cultures and showed that the hormone did not affect these parameters in either female- or male- derived samples. We then assessed the effect of E2 on the polarization of healthy CD4+ Tn cells into Th17 cells in vitro by measuring the expression of the Th17-defining transcription factor RORγt and the functional markers CCR6 and IL17. We found that E2 inhibited the expression of RORγt in Th17 polarization cultures from healthy young adult female and male donors, but that this inhibitory effect was lost with age. Additionally, preliminary results from young donor-derived samples suggest that the presence of E2 in polarization cultures might increase CCR6 and IL17 expression within the RORγt+ cells.
Our results suggest that E2 can help fine-tune the Th17 immune response in healthy young adults. Our next step will be to assess whether dysregulation of this signaling pathway in CD4+ T cells is a contributing factor in the development of SLE. We hope that better understanding the role of E2 signaling in SLE will help shed light on the sex bias and pathology of the disease, as well as help inform contraceptive choices for SLE patients.