Rheumatoid arthritis-associated RBPJ polymorphism alters memory CD4 super(+) T cells

• Published in: Human molecular genetics 2016-01, Vol.25 (2), p.404-417
• Main Authors: Orent, William, Mchenry, Allison R, Rao, Deepak A, White, Charles, Klein, Hans-Ulrich, Bassil, Ribal, Srivastava, Gyan, Replogle, Joseph M, Raj, Towfique, Frangieh, Michael, Cimpean, Maria, Cuerdon, Nicole, Chibnik, Lori, Khoury, Samia J, Karlson, Elizabeth W, Brenner, Michael B, De Jager, Philip, Bradshaw, Elizabeth M, Elyaman, Wassim
• Format: Article
• Language: English
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddv474

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 super(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 naive CD4 super(+) T cells. The rs874040 overlapping this chromatin state was associated with increased RBPJ expression in stimulated memory CD4 super(+) T cells from healthy subjects homozygous for the risk allele (CC) compared with memory CD4 super(+) T cells bearing the protective allele (GG). Transcriptomic analysis of rs874040 super(CC) memory T cells showed a repression of canonical Notch target genes IL (interleukin)-9, IL-17 and interferon (IFN) gamma 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 gamma expression in the rs874040 super(CC) memory CD4 super(+) T cells compared with their rs874040 super(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 gamma in response to Notch ligation in vitro. These findings demonstrate that the rs874040 super(CC) allele skews memory T cells toward a pro-inflammatory phenotype involving Notch signaling, thus increasing the susceptibility to develop RA.