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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.

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Ferreira, Ricardo C 
Castro Dopico, Xaquin 
Oliveira, João J 
Rainbow, Daniel B 
Yang, Jennie H 


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 Trp620 (rs2476601C>T) on Treg frequency. Trp620 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.



FOXP3, PD-1, PTPN22 Arg620Trp, autoimmunity, immunotherapy, regulatory T cells (Tregs), systemic lupus erythematosus (SLE), type I interferon, Adult, Aged, Aged, 80 and over, Alleles, Autoimmunity, Female, Forkhead Transcription Factors, Humans, Interleukin-2, Lupus Erythematosus, Systemic, Male, Middle Aged, Programmed Cell Death 1 Receptor, Protein Tyrosine Phosphatase, Non-Receptor Type 22, Risk, T-Lymphocytes, Regulatory, Young Adult

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Front Immunol

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Frontiers Media SA