EOMES-positive CD4⁺ T cells are increased in PTPN22 (1858T) risk allele carriers

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 T cells, 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, naïve human CD4⁺ T cells 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 T cells from healthy donors homozygous for the PTPN22 risk allele and correlated with a decreased number of naïve CD4⁺ T cells. There was no difference in the frequency of other CD4⁺ T-cell subsets (Th1, Th17, Tfh, Treg). Finally, an accumulation of EOMES⁺ CD4⁺ T cells 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⁺ T cells and identify EOMES⁺ CD4⁺ T cells as a relevant T-cell subset in RA pathogenesis.