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

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 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.

Influence of PTPN22 Allotypes on Innate and Adaptive Immune Function in Health and Disease

“…The authors offered a hypothesis that reconciles human data showing that PTPN22 620W is a gain-of-function; PTPN22 620W allows chronic signaling through the TCR that drives T cell exhaustion, causing T cells from PTPN22 620R/W and PTPN22 620W/W donors to be less responsive to stimulation through the TCR—a finding reported by most studies. This is supported by evidence that expression of PD-1, a marker of T cell exhaustion, is enhanced on CD4 + T eff and T regs in healthy PTPN22 620W/W donors compared to healthy PTPN22 620R/R donors ( 74 ). Furthermore, the reduced calcium flux seen in PTPN22 620R/W donors was most notable in memory CD4 + T cells with no difference observed in naïve CD4 + T cells; this could indicate that the experienced population is exhausted ( 76 ).…”

“…Most studies report no differences in most CD4 + T cells subsets (i.e., T H 1, T H 17, T H 1T H 17, T FH ) ( 73 ). However, PTPN22 620W/W donors had slightly-increased FOXP3 + CD4 + regulatory T cells(T regs ) (7.94% vs. 6.76%) compared to donors with the common PTPN22 620R/R allotype ( 74 , 75 ). It has been reported that PTPN22 620R/W donors have increased memory CD4 + T cells when compared to PTPN22 620R/R donors (about 50% vs. 41% respectively) with a concomitant decrease in naïve CD4 + T cells ( 76 ).…”

“…Differentiation of iT regs via treatment with IL-2/TGF-β1/αCD3/αCD28 was reduced with PTPN22 knockdown compared to control oligonucleotide transfected cells (% of CD4 T cells that are CD25 + FoxP3 + ; PTPN22 knockdown resulted in ~20% iTreg vs. control ~40%) ( 33 ). No direct clinical studies have shown how PTPN22 620 allotypes influence iT reg differentiation; however, healthy PTPN22 620W/W donors have increased CD4 + T regs compared to healthy PTPN22 620R/R donors (7.94% vs. 6.76%) implying that PTPN22 620W might potentiate iT reg development ( 74 , 75 ). Although PTPN22 620W/W donors have slightly more CD4 + T regs , these T regs exhibit a reduced capacity to inhibit IFNγ secretion from conventional T cells compared to those from PTPN22 620R/R donors ( 47 , 76 ).…”

Spatial Regulation of T-Cell Signaling by Programmed Death-Ligand 1 on Wireframe DNA Origami Flat Sheets

“… 15 , 16 Conversely, PD-1 agonists have been proposed as therapies for autoimmune diseases. 17 Therefore, there is a need to gain a fuller understanding of the mechanisms of PD-1-mediated inhibition of T-cell signaling to improve the effects of PD-1 modulators in the clinic.…”

DataSheet_1.pdf

“…Alternatively, CTLA4, which is highly expressed after T cell activation, acts as a competitor of CD28 and induces a state of T cell unresponsiveness and anergy (26)(27)(28). PD1, a novel co-inhibitory member of the B7/CD28 family, is engaged by PD-L1 to inhibit T cell activation (29)(30)(31). The PD1 inhibitor has been used in the clinical treatment of cancer to cancel the limitation on T cell-mediated anti-cancer responses (32)(33)(34).…”