Dataset Information

Sustained low-dose interleukin-2 therapy alleviates pathogenic humoral immunity via elevating the Tfr/Tfh ratio in lupus.

ABSTRACT:

Objectives

Low-dose interleukin-2 (IL-2) has shown promising clinical benefits in the treatment of systemic lupus erythematosus (SLE), but how this therapy alleviates pathogenic humoral immunity remains not well understood. The dilemma is that IL-2 can suppress both follicular helper and regulatory T (Tfh and Tfr) cells, which counteract each other in regulating autoantibody production.

Methods

Female NZB/W F1 mice received recombinant human IL-2 (3 × 10⁴ IU/dose) in three treatment regimens: (1) short, daily for 7 days; (2) medium, daily for 14 days, and (3) long, every second day for 28 days. Tfh (Foxp3^-CXCR5⁺Bcl6⁺), Tfr (Foxp3⁺CXCR5⁺Bcl6⁺), germinal centre (GC, B220⁺GL-7⁺Fas⁺) and antibody-secreting cell (ASC, B220^-CD138⁺TACI⁺) were analysed by flow cytometry. Serum anti-dsDNA level was determined by ELISA. Kidney pathology was evaluated by H&E and immunofluorescence staining. Circulating Tfh and Tfr cells in SLE patients treated with low-dose IL-2 from a previous clinical trial (NCT02084238) was analysed.

Results

Low-dose IL-2 treatment consistently increased Tfr/Tfh ratio in mice and SLE patients, because of a stronger suppression on Tfh cells than Tfr cells. Three treatment regimens revealed distinct immunological features. Tfh suppression was observed in all regimens, but Tfr suppression and GC reduction were recorded in just medium and long regimens. Only the long treatment regimen resulted in inhibited ASC differentiation in spleen, which was accompanied by reduced anti-dsDNA titres and ameliorated kidney pathology.

Conclusion

Low-dose IL-2 therapy increases the Tfr/Tfh ratio, and a less frequent and prolonged treatment can alleviate pathogenic humoral immunity and improve renal function.

SUBMITTER: Liang K

PROVIDER: S-EPMC8169300 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: Follicular helper T (Tfh) cells and follicular regulatory T (Tfr) cells are essential for B cell differentiation, germinal center formation, and humoral immune responses. Immunity and inflammation have been thought to be involved in Parkinson's disease (PD). In this study, we aimed to identify whether circulating Tfh and Tfr (cTfh and cTfr) cells contribute to PD. Methods: Thirty-nine PD patients and 26 health controls (HCs) were enrolled. The numbers of cTfh (CD4+CXCR5+PD-1+) cells and cTfr (CD4+CXCR5+CD25hiCD127low) cells were analyzed via flow cytometry. The serum concentrations of interleukin (IL)-4, IL-10, IL-21, and transforming growth factor (TGF)-β were examined by cytometric bead array. Results: The percentage of cTfh cells among CD4+ T cells in PD patients was significantly higher than that in HCs [3.68% (2.64-5.70%) vs. 1.94% (1.32%-2.99%), P < 0.001], while the percentage of cTfr cells among CD4+ T cells in PD patients was slight decreased but without significance [1.05% (0.62-1.54%) vs. 1.3% (0.63-1.90%), P > 0.05]. The percentage of CD19+ B cells in peripheral blood mononuclear cells was significantly lower in PD patients than in HCs [5.35% (4.13-9.38%) vs. 8.68% (5.61-12.93%), P = 0.014]. The serum concentrations of IL-4, IL-10, IL-21, and TGF-β in PD patients did not differ significantly from those in HCs (P > 0.05). There was a positive trend of the correlation between the number of cTfh and the serum IL-4 concentrations in PD patients (P = 0.032, r = 0.353). There was a positive trend of the correlation between the number of cTfr and the serum IL-10 concentrations in PD patients (P = 0.047, r = 0.328), A positive trend of the correlation were found for the serum concentration of IL-21 with H-Y stage (r = 0.356, P = 0.026) and UPDRS-III score (r = 0.347, P = 0.030). Conclusions: These results indicate that an imbalance of cTfh and cTfr cells may be involved in the chronic progression of PD, and IL-21 may be a biomarker for monitoring the severity of this disease.