Background B cells may have a negative regulatory role, mainly mediated by interleukin 10 (IL-10). We recently showed that regulatory B cell functions are impaired in patients with rheumatoid arthritis (RA) and that a proliferation inducing ligand (APRIL) transgenic mice are protected against collagen induced arthritis.
Objectives We aimed to explore the effect of APRIL on normal human B cell IL-10 production.
Methods CpG induced IL-10 B cell production was compared in presence or absence of APRIL and B lymphocyte stimulating factor (BLys). The expression of the BLyS and APRIL receptor transmembrane activator and CAML interactor (TACI) and of BLyS specific receptor (BAFF-R) was compared between IL-10 producing and non-producing B cells. The effect of APRIL stimulated B cells on T cell cytokine production was analyzed after 3 days of co-culture. Signaling pathways of B cells activated by CpG and APRIL were analyzed by western blot. Similar experiments were performed on cells of RA patients.
Results APRIL but not BLyS promotes IL-10 production by B cells (9.5 [6.8-13.2] vs 6.2 [3.9-7.0] vs 4.2 [3.3-8.0] % for APRIL, BLyS and culture medium alone respectively, APRIL vs media p=0.002 and APRIL vs BLyS p=0.007).The effect was abrogated by co-culturing of TACI-Fc. IL-10 producing B cells expressed significantly more TACI (7.1 [5.5-16.8] vs 2.4 [1.9-7.8]%; p=0.016) and less BAFF-R (2.3 [2.0-2.5] vs 2.7 [2.3-2.8] of mean fluorescence intensity; p=0.021) than non- IL-10 producing B cells. APRIL stimulated B cells decreased TNF-α (-36±13%, p=0.02) and IFN-γ (-14±3%; p=0.02) secretion of T cells compared to non-stimulated B cells but not IL-17 production (-14±14%, p=0.31). APRIL further stimulated CpG activated STAT3, ERK and JNK pathways. APRIL also promoted IL-10 production of B cells in RA patients and similar pattern of APRIL and BLyS receptors on IL-10 producing B cells were observed in RA patients and in controls.
Conclusions We show for the first time that APRIL but not BLyS promotes IL-10 production by B cells and enhances the regulatory role of B cells on T cells by decreasing TNF-a and IFN-g by T cells. IL-10 producing B cells of RA patients are responsive to APRIL suggesting a possible therapeutic application by expanding B10 cells of these patients.
Disclosure of Interest None declared
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