Sexual dimorphism in mechanisms controlling development of CD4+ T cell response in collagen-induced arthritis

Abstract

Introduction: Considering sex bias in rheumatoid arthritis prevalence, influence of biological sex on the disease development in Dark Agouti rat collagen II (CII)−induced arthritis (CIA) model of the human disease was examined. Methods: Sex bias in CD4+ T cell responses in inguinal (draining the site of immunization in preclinical CIA) and popliteal (draining inflamed joints at the peak of CIA) lymph nodes (LNs) and mechanisms controlling their development were examined using flow cytometry and/or ELISA/qRT−PCR. Results: In both inguinal and popliteal LNs greater number of CD4+CD25+Foxp3− cells, presumably activated effector T cells, was found in females compared with males, and they exhibited greater CII−specific proliferation. Consistently, more IL−17+, IFN−γ+ and IL−17+IFN−γ+ T cells were retrieved from both inguinal and popliteal female rat LNs. Moreover, more GM−CSF+ and IL−17+IFN−γ+GM−CSF+ T cells were retrieved from female compared with male rat popliteal LNs. On the other hand, lower frequency of PD−1+ cells among CD4+CD25+Foxp3+ regulatory T cells (Tregs) from female popliteal and inguinal LNs suggested lower suppressive capacity of their Tregs. Additionally, from female rat popliteal LNs fewer Tregs were recovered. Furthermore, the number of regulatory LN B10 cells was lower in females. Moreover, compared with males, in females was shifted LN INF−γ+/IL−4+ T−cell ratio towards the former, and accordingly serum CII−specific IgG2a/IgG1 antibody ratio was shifted towards pathogenic IgG2a antibodies. Conclusion: The study suggests that a less efficient control of (auto)immune Th1/Th17 cell responses during CIA development contributes to sex bias in the susceptibility to CIA.