Abstract
B cell-derived interleukin-10 (IL-10) production has been described as a hallmark for regulatory function in B lymphocytes. However, there is an ongoing debate on the origin of IL-10-secreting B cells and lack of specific surface markers has turned into an important obstacle for studying human B regulatory cells. In this study, we propose that tumor necrosis factor receptor 2 (TNFR2) expression can be used for enrichment of IL-10-secreting B cells. Our data confirm that IL-10 production can be induced by TLR9 stimulation with CpG ODN and that IL-10 secretion accompanies differentiation of peripheral blood B cells into plasma blasts. We further show that CpG ODN stimulation induces TNFR2 expression, which correlates with IL-10 secretion and terminal differentiation. Indeed, flow cytometric sorting of TNFR2+ B cells revealed that TNFR2+ and TNFR2− fractions correspond to IL-10+ and IL-10− fractions, respectively. Furthermore, CpG-induced TNFR2+ B cells were predominantly found in the IgM+ CD27+ B cell subset and spontaneously released immunoglobulin. Finally, our data corroborate the functional impact of TNFR2 by demonstrating that stimulation with a TNFR2 agonist significantly augments IL-10 and IL-6 production in B cells. Altogether, our data highlight a new role for TNFR2 in IL-10-secreting human B lymphocytes along with the potential to exploit this finding for sorting and isolation of this currently ill-defined B cell subset.
Highlights
The first observation of regulatory function of B cells producing interleukin-10 (IL-10) was demonstrated in mice with experimental autoimmune encephalomyelitis in 1996 by Janeway and colleagues [1]
The graph summarizes the results from n = 5 independent donors (*p < 0.05, **p < 0.01, n.s., not significant). (C) TNF receptor 1 (TNFR1) and tumor necrosis factor receptor 2 (TNFR2) expression on total CD19+ B cells was analyzed by flow cytometry in freshly isolated B cells (d0) and on days 3 and 5 after stimulation with CpG ODN
We investigated whether expression of TNFR2 could be used to characterize and purify human IL-10-secreting B cells
Summary
The first observation of regulatory function of B cells producing interleukin-10 (IL-10) was demonstrated in mice with experimental autoimmune encephalomyelitis in 1996 by Janeway and colleagues [1]. Different subpopulations of IL-10-secreting B cells have been described in the mouse and their regulatory capacity has been demonstrated in models of infection and autoimmune diseases [2,3,4,5]. It was previously shown that a distinct subpopulation of B lymphocytes producing anti-inflammatory cytokines such as IL-10 could be differentiated from peripheral blood B cells via TLR9 stimulation with CpG DNA [6, 7]. IL-10secreting B cells were described in different types of infection including polyclonal B cell expansion triggered by Staphylococcus aureus [8], HIV patients [9, 10], and murine schistosomiasis. Various studies indicated their reduced representation in peripheral blood of patients with autoimmune diseases and immune deficiencies [13,14,15]
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