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

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ID: 71719
2019
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Abstract
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 CD4FOXP3 cells in circulation owing to a specific expansion of thymically-derived FOXP3HELIOS Tregs with a demethylated 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 (rs2476601C>T) on Treg frequency. Trp 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.
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Authors 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;
Journal Frontiers in immunology
Year 2019
DOI
10.3389/fimmu.2019.02606
URL
Keywords
immunotherapy autoimmunity pd-1 foxp3 ptpn22 arg620trp regulatory t cells (tregs) systemic lupus erythematosus (sle) type i interferon

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