Details

Autor(en) / Beteiligte

• Ferreira, Ricardo C.
• Castro Dopico, Xaquin
• Oliveira, João J.
• Rainbow, Daniel B.
• Yang, Jennie H.
• Trzupek, Dominik
• Todd, Sarah A.
• McNeill, Mhairi
• Steri, Maristella
• Orrù, Valeria
• Fiorillo, Edoardo
• Crouch, Daniel J. M.
• Pekalski, Marcin L.
• Cucca, Francesco
• Tree, Tim I.
• Vyse, Tim J.
• Wicker, Linda S.
• Todd, John A.

Titel

Chronic Immune Activation in Systemic Lupus Erythematosus and the Autoimmune PTPN22 Trp620 Risk Allele Drive the Expansion of FOXP3+ Regulatory T Cells and PD-1 Expression

Ist Teil von

• Frontiers in immunology, 2019-11, Vol.10, p.2606-2606

Ort / Verlag

Frontiers Media S.A

Erscheinungsjahr

2019

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• In systemic lupus erythematosus (SLE), perturbed immunoregulation underpins a pathogenic imbalance between regulatory and effector CD4 + T-cell activity. However, to date, the characterization of the CD4 + regulatory T cell (Treg) compartment in SLE has yielded conflicting results. Here we show that patients have an increased frequency of CD4 + FOXP3 + cells in circulation owing to a specific expansion of thymically-derived FOXP3 + HELIOS + Tregs with a demethylated FOXP3 Treg-specific demethylated region. We found that the Treg expansion was strongly associated with markers of recent immune activation, including PD-1, plasma concentrations of IL-2 and the type I interferon biomarker soluble SIGLEC-1. Since the expression of the negative T-cell signaling molecule PTPN22 is increased and a marker of poor prognosis in SLE, we tested the influence of its missense risk allele Trp 620 (rs2476601C>T) on Treg frequency. Trp 620 was reproducibly associated with increased frequencies of thymically-derived Tregs in blood, and increased PD-1 expression on both Tregs and effector T cells (Teffs). Our results support the hypothesis that FOXP3 + Tregs are increased in SLE patients as a consequence of a compensatory mechanism in an attempt to regulate pathogenic autoreactive Teff activity. We suggest that restoration of IL-2-mediated homeostatic regulation of FOXP3 + Tregs by IL-2 administration could prevent disease flares rather than treating at the height of a disease flare. Moreover, stimulation of PD-1 with specific agonists, perhaps in combination with low-dose IL-2, could be an effective therapeutic strategy in autoimmune disease and in other immune disorders.