Ca²⁺‐related signaling events influence TLR9‐induced IL‐10 secretion in human B cells

Abstract

Suppressory B-cell function controls immune responses and is mainly dependent on IL-10 secretion. Pharmacological manipulation of B-cell-specific IL-10 synthesis could, thus, be therapeutically useful in B-cell chronic lymphocytic leukemia, transplantation, autoimmunity and sepsis. TLR are thought to play a protagonistic role in the formation of IL-10-secreting B cells. The aim of the study was to identify the molecular events selectively driving IL-10 production in TLR9-stimulated human B cells. Our data highlight the selectivity of calcineurin inhibitors in blocking TLR9-induced B-cell-derived IL-10 transcription and secretion, while IL-6 transcription and release, B-cell proliferation, and differentiation remain unaffected. Nevertheless, TLR9-induced IL-10 production was found to be independent of calcineurin phosphatase activity and was even negatively regulated by NFAT. In contrast to TLR9-induced IL-6, IL-10 secretion was highly sensitive to targeting of spleen tyrosine kinase ( Eur. J. Immunol. 2014. 44: 1285-1298 [7]. However, the mechanisms underlying this suppressory B-cell function were less well understood. To date, it is well accepted that the hallmark of B-cell regulatory function is the anti-inflammatory cytokine . IL-10-producing B cells arise in different contexts, among them B-cell chronic lymphocytic leukemia (B-CLL), infections, and the immune response to apoptotic cells [9][10][11]. They can limit ongoing T-cell responses [12]. While exclusive lack of TLR adaptor MyD88 in B lymphocytes leads to development of chronic EAE or aggravation of Salmonella infection [10], loss of B-cell-specific IL-10 drives autoimmunity in TLR9-deficient mice [13].Further reports propose that formation of plasma blasts coincides with release of 14]. This highlights the possibility that in B cells IL-10 production is triggered in an Ag-specific manner and might selectively target Ag-specific T cells. This would discriminate the function of B-cell-derived IL-10 from that produced by myeloid cells. As a consequence, specific pharmacological intervention with B-cell-derived IL-10 could represent a promising strategy to protect from destructive T-cell responses to both auto-and alloantigen while preserving immunity to infection.Transcriptional regulation of IL-10 synthesis is cell type specific [15]. In B cells, IL-10 production has been investigated upon BCR activation and in leukemia. The studies suggest a role of calcium sensors and NFAT transcription factors (TF) [11,16]. However, little is known on the regulation of B-cell-derived IL-10 production and in particular in response to TLR9 stimulation. The objective of the present study was to analyze the molecular mechanisms regulating IL-10 production in B cells challenged with TLR9 agonists. Results CpG oligodeoxynucleotides (ODN) and BCR cross-linking represent potent IL-10 inducersIn this study, we were interested in the molecular mechanisms mediating B-cell-derived release of IL-10 upon stimulation of TLR9. BCR-, TLR-, and CD40-signaling have all been implicate...

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