Sexual dimorphism in Th17/Treg axis in lymph nodes draining inflamed joints in rats with collagen-induced arthritis

• Published in: Brain, behavior, and immunity behavior, and immunity, 2019-02, Vol.76, p.198-214
• Main Authors: Dimitrijević, Mirjana, Arsenović-Ranin, Nevena, Kosec, Duško, Bufan, Biljana, Nacka-Aleksić, Mirjana, Pilipović, Ivan, Leposavić, Gordana
• Format: Article
• Language: English
• Subjects: Animals; Arthritis, Experimental - immunology; Arthritis, Rheumatoid - immunology; Bregs; Collagen - pharmacology; Collagen-induced arthritis; Cytokines - metabolism; Disease Models, Animal; Female; IL-35; Inflammation - immunology; Inflammation - metabolism; Interleukin-17 - metabolism; Lymph Nodes - immunology; Lymph Nodes - metabolism; Male; Rats; Rats, Inbred Strains; Sex Characteristics; Sex differences; Sex Factors; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Th17 Cells - immunology; Th17 Cells - metabolism; Th17/Treg axis plasticity
• ISSN: 0889-1591; 1090-2139
• DOI: 10.1016/j.bbi.2018.11.311

•Female rats develop more severe collagen-induced arthritis (CIA) than male rats.•Th17 cell response in lymph nodes draining inflamed joints is greater in females.•Th17 cell redifferentiation into highly pathogenic cells is favored in females.•Treg transdifferentiation into IL-17-secreting cells is diminished in females.•Sexual dimorphism in Th17/Treg axis correlates with sex bias in the severity of CIA. Collagen type II-induced arthritis (CIA) in Dark Agouti rats, a model of rheumatoid arthritis (RA), reproduces sexual dimorphism in the incidence and severity of the human disease. Th17 cells are central in the induction/propagation of autoimmune inflammation in CIA and RA. To assess mechanisms underlying this dimorphism in CIA rats, in lymph nodes draining inflamed joints and adjacent tissues (dLNs) from CIA rats of both sexes Th17/CD25+Foxp3+CD4+ T-regulatory cell (Treg) ratio, Th17 cell redifferentiation in functionally distinct subsets and Treg transdifferentiation into IL-17-producing cells (exTregs) were examined. In female rats (developing more severe CIA than their male counterparts) the higher frequency of all Th17 cells (reflecting partly their greater proliferation), followed by the higher frequency of highly pathogenic IFN-γ/GM-CSF-co-producing cells, but lower frequency of less pathogenic/immunoregulatory IL-10-producing cells among them was found. Additionally, compared with male rats, in female rats the lower frequency of Tregs was observed. Moreover, Tregs from female rats exhibited diminished proliferative and suppressive capacity (judging by PD-1 expression) and enhanced conversion into IL-17-producing cells. Given that TGF-β concentration was comparable in collagen-type II-stimulated dLN cell cultures from female and male rats, the shift in Th17/Treg ratio followed by augmented Th17 cell redifferentiation into IFN-γ/GM-CSF-co-producing cells and Treg transdifferentiation into IL-17-producing cells in female rats was associated with increased concentration of IL-6 in female rat dLN cell cultures, and the higher frequency of IL-1β- and IL-23-producing cells among their dLN cells. The lower frequency of IL-10-producing B cells, presumably B regulatory cells (Bregs) could also contribute to the shift in Th17/Treg ratio in female rat compared with male rat dLNs. Consistently, the lower expression of IL-35 (the cytokine promoting Treg expansion directly and indirectly, by favoring Breg expansion and conversion into IL-10/IL-35-producing cells)