Journal
EUROPEAN JOURNAL OF IMMUNOLOGY
Volume 48, Issue 4, Pages 655-669Publisher
WILEY
DOI: 10.1002/eji.201747296
Keywords
4-1BB; CD4(+) Tcells; cytotoxic T lymphocytes; Perforin-1; Rheumatoid Arthritis (RA)
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Funding
- Science for Life Laboratory
- Knut and Alice Wallenberg Foundation
- National Genomics Infrastructure - Swedish Research Council
- Uppsala Multidisciplinary Center for Advanced Computational Science
- FP7 Masterswitch [HEALTH-F2-2008-223404]
- IMI BTCure [115142-2]
- Swedish research council
- Swedish association against rheumatism
- European Research Council (ERC) [260167]
- King Gustaf V 80-year Foundation
- Ulla and Gustaf af Ugglas foundation
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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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