Sex Hormones Regulate T-Cell Responses Associated With Rheumatoid Arthritis

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by sustained synovial inflammation contributing to bone erosion and loss of joint function. The pathological response of infiltrated T cell subsets, followed by the formation of ectopic lymphoid microstructures in the synovial tissue, promotes RA progression and exacerbates disease severity. Two major hallmarks of RA pathogenesis are dysregulated peripheral tolerance and aberrant pro-inflammatory responses due to the secretion of pro-inflammatory cytokines within the RA synovium. Interestingly, regulatory T cells (Tregs) and Th2, which play a vital role in maintaining immune homeostasis and peripheral tolerance, are reduced in numbers or become functionally impaired within the RA synovium, resulting in Th1/Th2 and Th17/Treg imbalance. Additionally, CD8+ T cells have also emerged as major mediators of synovial inflammation and autoantibody production in RA. Women display higher susceptibility to developing RA, and the chances of disease pathogenesis increase steadily from menarche to menopause, possibly due to a decline in sex-hormone levels. Although the decline in female sex hormones has been implicated in aberrant T cell responses and RA progression, the impact of hormone levels on the molecular signaling pathways regulating T cell differentiation and homeostasis, and subsequently the disease pathogenesis in premenopausal and postmenopausal women, remains incompletely understood. Hence, this review aims to provide a comprehensive understanding of the differential control of sex hormone levels in regulating T cell responses, including T cell plasticity and functions associated with RA progression. We further discuss the underlying signaling mechanisms where declining postmenopausal sex-hormone levels promote aberrant T-cell activation and effector functions within the RA synovium, thereby disrupting peripheral tolerance and immune homeostasis, and contributing to RA pathogenesis. A critical understanding of sex hormone-mediated regulation of T cell responses associated with RA may unveil novel hormone-targeted therapeutic strategies to limit disease progression.