Potential Impact of B Cells on T Cell Function in Multiple Sclerosis

Table 1

Cytokines produced by B cells.

Cytokine	effects	Demonstration
IL-10	Inhibits T cell proliferation, IFN-γ and IL-2 production while enhancing Th2 responses [62–64]	Purified CD19+ peripheral human B cells produce IL-10 protein after dual stimulation with CpG and CD40L [65]. Maximal IL-10 production was noted with CD40L alone, compared to dual stimulation of BCR cross-link and CD40L [66]. IL-10 was secreted primarily by naïve CD19+CD27− B cells [39].
TGF-β	Induces tolerance and inflammation-dependent additional cytokine signals; IgA class switch and dampening NK activity [67–69]; development of Th17 and Treg cells [70]	Human total CD19+ B cells produce TGF-β mRNA in response to BCR cross-linking [71]. Anti-immunoglobulin treatment of murine B cell lymphomas induces active TGF-β [71].
LT-α	Required for the formation of germinal centers and follicles, upregulation of adhesion molecules [72, 73]	Purified human CD19+ B cells produce significant amounts of LT-α after dual stimulation with CpG and CD40L [65]. Maximal production was observed after dual stimulation of BCR cross-link and CD40L [66]. LT-α was secreted primarily by memory CD19+CD27+ B cells [39].
TNF-α	Increases IL-2 receptor and HLA-DR expression; induces T cell proliferation and IFN-γ production [74, 75]	Human CD19+ B cells produce TNF-α in response to CpG stimulation alone or in combination with CD40L [65, 76], or dual stimulation of BCR cross-link and CD40L [66]. TNF-α was secreted primarily by memory CD19+CD27+ B cells [39, 77].
IL-12	Critical for Th1 development, induces IFNγ production, enhances NK and CTL activity, inhibits Th2 development, and inhibits IgE class switching [78]	Human total CD19+ B cells produce IL-12p70 in response to dual stimulation with CpG and CD40L, but not in response to CpG (or CD40L) alone [65].
IL-6	Mediates early inflammation; activates endothelium and acts as growth and recruitment factor for lymphocytes [79–82]	Mediates early inflammation, activates endothelium, and acts as growth and recruitment factor for lymphocytes [79–81].
IFN-γ	Amplifies IFN-𝛾 production; activates CTL and NK; critical for Th1 response [83, 84]	EBV-transformed B cell lines constitutively express IFN-γ as measured by qPCR [85]. PMA or IL-2 stimulation of EBV or B cell tumor lines induces IFN-γ [86].
IFN-α	Upregulates inflammatory cytokines [87]; implicated in the pathogenesis of several inflammatory autoimmune diseases including RA and IBD [88–90]	Purified human CD19+ B cells produce IFN-α transcripts in response to TLR8 agonist, but only in the first 24 hours post-stimulation [91]. Interestingly IFN-β, another type 1 interferon, is used as a treatment for RRMS.