Semaphorin 4D induces an imbalance of Th17/Treg cells by activating the
aryl hydrocarbon receptor in ankylosing spodylitis
Abstract
Objectives: to investigate the mechanism by which Sema4D affects the
pathogenic progress of ankylosing spondylitis (AS). Methods: Soluble
Sema4D (sSema4D) levels in serum were analyzed by enzyme-linked
immunosorbent assay. The cell surface levels and transcripts of Sema4D
were evaluated in CD4+ and CD19+ cells from the AS patients and healthy
individuals. The mRNA expression levels were assessed by quantitative
polymerase chain reaction (qPCR). The proportions of Treg cells and
IL-17-producing T-cells (Th17 cells) differentiated from CD4+ T cells
were analyzed by flow cytometric analysis. The aryl hydrocarbon receptor
(AhR) agonistic effect of Sema4D was detected by analyzing the
activation of downstream signaling pathways and target genes using
Luciferase and EROD assay. Results: Levels of sSema4D were elevated in
both serum from AS patients, and clinical features markers were
correlated with serum sSema4D levels. Sema4D facilitated CD4+ T cells
proliferation and Th17 cells differentiation and inhibited Treg cells
differentiation by enhancing RORγt expression and reducing Foxp3
expression, with increasing expression and secretion of IL-17 and IL-22.
It induced the expression and activity of AhR target gene CYP1A1 and XRE
reporter activity via interaction with CD72. Conclusions: These findings
indicate that Sema4D as a potent activator of T cells in the immune
response contributes to the inflammation of AS by inducing imbalance in
Th17 and Treg cell populations in an AhR-dependent manner, suggesting it
is a crucial participant in AS pathogenesis.