Eomes-Positive Cd4(+) Tcells Are Increased In Ptpn22 (1858t) Risk Allele Carriers
EUROPEAN JOURNAL OF IMMUNOLOGY(2018)
摘要
The presence of the PTPN22 risk allele (1858T) is associated with several autoimmune diseases including rheumatoid arthritis (RA). Despite a number of studies exploring the function of PTPN22 in Tcells, the exact impact of the PTPN22 risk allele on T-cell function in humans is still unclear. In this study, using RNA sequencing, we show that, upon TCR-activation, naive human CD4(+) Tcells homozygous for the PTPN22 risk allele overexpress a set of genes including CFLAR and 4-1BB, which are important for cytotoxic T-cell differentiation. Moreover, the protein expression of the T-box transcription factor Eomesodermin (EOMES) was increased in Tcells from healthy donors homozygous for the PTPN22 risk allele and correlated with a decreased number of naive CD4(+) Tcells. There was no difference in the frequency of other CD4(+) T-cell subsets (Th1, Th17, Tfh, Treg). Finally, an accumulation of EOMES(+)CD4(+) Tcells was observed in synovial fluid of RA patients with a more pronounced production of Perforin-1 in PTPN22 risk allele carriers. Altogether, we propose a novel mechanism of action of PTPN22 risk allele through the generation of cytotoxic CD4(+) Tcells and identify EOMES(+)CD4(+) Tcells as a relevant T-cell subset in RA pathogenesis.
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关键词
4-1BB, CD4(+) Tcells, cytotoxic T lymphocytes, Perforin-1, Rheumatoid Arthritis (RA)
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