Background/Purpose:

Human FoxP3⁺ Th-cells are heterogeneous in function and include not only suppressive cells (T_Regs) but also non-suppressive cells that abundantly secrete proinflammatory cytokines. We have previously shown that FoxP3⁺ Th-cells were increased in GPA-patients during remission as compared to healthy controls (HCs). In this group of patients, however, we observed a defective suppressor function of T_Regs, and an increase in the percentage of Th-17 cells. These observations make it tempting to investigate whether increased FoxP3⁺ Th-cells in GPA-patients are attributed to an increase in the cytokine-secreting non-suppressive FoxP3⁺Th-cells.

Methods:

Peripheral blood mononuclear cells (PBMCs) were isolated from 46 GPA-patients in remission and from 22 age- and sex-matched HCs. Expression of CD4, CD45RO, and FoxP3 were determined by flow cytometric analysis. The expression levels of FoxP3 and CD45RO were used for distinction between activated suppressor T_Regs (FoxP3^HighCD45RO⁺; _AST_Reg), resting suppressor T_Regs (FoxP3^LowCD45RO^–; _RST_Reg), and cytokine-secreting non-suppressor T_Regs (FoxP3^LowCD45RO⁺; _NONT_Reg) cells. Intracellular expression of IFNg, IL-17, and IL-21 were determined in the various FoxP3⁺ Th-cell subsets after in vitroactivation of PBMCs by PMA and Ca-Ionophore.

Results:

A significant increase in the frequency of _NONT_Reg cells was observed in GPA-patients as compared with HCs, whereas no differences were detected in _RST_Reg– and _AST_Reg cells between GPA-patients and HCs. The distribution of _RST_Reg– and _NONT_Reg cells did not differ between ANCA-negative and ANCA-positive patients, whereas lower percentages of _AST_Reg cells were observed in ANCA-positive patients as compared to ANCA-negative patients and HCs. Importantly, a significant increase in the percentage of IL-17⁺ and IL-21⁺ cells was seen within the _NONT_Regcells from ANCA-positive patients (n= 9) when compared to ANCA-negative (n= 10) and HCs (n= 12), whereas no differences were found between ANCA-negative and HCs.   

Conclusion:

Increased FoxP3 expression in Th-cells from GPA-patients is related to an increase in a subset of non-suppressive Th-cells.  Increased production of IL-17 and IL-21 cytokines, in _NONT_Reg cells from ANCA-positive patients points towards FoxP3⁺ effector cells and decrease in suppressive T_Reg cells in relation to ANCA production.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/unraveling-the-identity-of-foxp3-regulatory-t-cells-in-gpa-patients/