Session Type: Abstract Submissions (ACR)
Background/Purpose: T helper 17 (Th17) cells are a subset of pro-inflammatory CD4+ T cells implicated in a number of inflammatory arthritides including the Spondyloarthritides (SpAs). Ankylosing Spondylitis (AS), the commonest spondyloarthropathy, has genetic associations both with HLA-B27 and with IL-23 receptor (IL-23R) single nucleotide polymorphisms (SNPs), however the link remains unexplained. We have previously shown that KIR3DL2+ CD4+ T cells are expanded in the peripheral blood of individuals with AS. The aim of the study was to further characterize KIR3DL2+ CD4+ T cells and to correlate IL-23R expression on KIR3DL2+ CD4+ T cells to IL-23R genotype.
The frequency and expression level of Th17 markers IL-23R, IL-1R and CCR6 on peripheral blood KIR3DL2+ CD4+ T cells was investigated by flow cytometry (n=15) and confirmed by qRT-PCR (n=3). IL-23R expression on paired peripheral blood and synovial fluid samples from SpA patients was investigated by flow cytometry (n=3). Cytokine production by anti-CD2/3/28-stimulated FACS-sorted KIR3DL2+ and KIR3DL2- CD4+ T cells was investigated using multiplex bead analysis. Immunochip GWAS and ENCODE data were integrated to predict functional SNPs in the IL-23R secondary region of association.
Results: KIR3DL2+ CD4+ T cells were increased in the peripheral blood of HLA-B27+ AS patients, as compared to HLA-B27- healthy controls (p<0.001, n= 15), confirming previous findings. KIR3DL2+ CD4+ T cells were enriched for expression of the Th17 phenotypic markers IL23R (p<0.0001, n=15), CCR6 (p<0.0001, n=15) and IL-1R (p<0.0001, n=15), compared to KIR3DL2- CD4+ T cells. IL-23R expression levels were also increased on KIR3DL2+ CD4+ T cells compared to KIR3DL2- CD4+ T cells from AS patients (p<0.0001, n=15). SNPs in three (non-coding) putative regulatory regions (PRRs) of IL-23R were identified (PRR1-3). The presence of the AS risk-associated allele at PRR1 correlated with increased expression of IL-23R on KIR3DL2+ CD4+ T cells (p=0.031, n=13). KIR3DL2+ CD4+ T cells accounted for the majority of peripheral blood CD4+ T cell IL-23R expression in AS patients, and this was significantly greater compared to HLA-B27- healthy controls (p<0.01, n=15). KIR3DL2+ CD4+ T cells from AS patients produced significantly more IL-17 than KIR3DL2- CD4+ T cells (p=0.037, n=7). IL-17 production significantly increased in the presence rIL-23 and rIL-1 (p=0.029, n=7). Lastly IL-23R expression was increased on KIR3DL2+ CD4+ T cells from SpA synovial fluid samples compared to match peripheral blood samples when available (p=0.017, n=3).
Conclusion: KIR3DL2-expressing cells constitute the majority of peripheral blood CD4+ T IL-23R-expressing cells in AS and produce increased levels of IL-17. Correlation of IL-23R expression on KIR3DL2+ CD4+ T cells with putative regulatory SNPs suggest genetic and epigenetic control of IL-23R expression may contribute to the pathogenesis of AS.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/increased-il-23-receptor-expression-is-observed-on-kir3dl2-cd4-t-cells-in-ankylosing-spondylitis-and-correlates-with-il-23r-polymorphisms/