Publication Date:
2016-01-09
Description:
Notch signaling has recently emerged as an important regulator of immune responses in autoimmune diseases. The recombination signal-binding protein for immunoglobulin kappa J region (RBPJ) is a transcriptional repressor, but converts into a transcriptional activator upon activation of the canonical Notch pathway. Genome-wide association studies of rheumatoid arthritis (RA) identified a susceptibility locus, rs874040 CC , which implicated the RBPJ gene. Here, chromatin state mapping generated using the chromHMM algorithm reveals strong enhancer regions containing DNase I hypersensitive sites overlapping the rs874040 linkage disequilibrium block in human memory, but not in naïve CD4 + T cells. The rs874040 overlapping this chromatin state was associated with increased RBPJ expression in stimulated memory CD4 + T cells from healthy subjects homozygous for the risk allele (CC) compared with memory CD4 + T cells bearing the protective allele (GG). Transcriptomic analysis of rs874040 CC memory T cells showed a repression of canonical Notch target genes IL (interleukin)-9, IL-17 and interferon (IFN) in the basal state. Interestingly, activation of the Notch pathway using soluble Notch ligand, Jagged2-Fc, induced IL-9 and IL-17A while delta-like 4Fc, another Notch ligand, induced higher IFN expression in the rs874040 CC memory CD4 + T cells compared with their rs874040 GG counterparts. In RA, RBPJ expression is elevated in memory T cells from RA patients compared with control subjects, and this was associated with induced inflammatory cytokines IL-9, IL-17A and IFN in response to Notch ligation in vitro . These findings demonstrate that the rs874040 CC allele skews memory T cells toward a pro-inflammatory phenotype involving Notch signaling, thus increasing the susceptibility to develop RA.
Print ISSN:
0964-6906
Electronic ISSN:
1460-2083
Topics:
Biology
,
Medicine
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