Figure 3.

Effects of IL-21 on human naïve B cells in vitro. When human naïve B cells are stimulated with CD40L together with IL-21, they were found to undergo intense proliferation. This was followed by induction of Ig class switching – predominantly to IgG₃ and IgG₁; a lesser extent to IgA₁ – as determined by acquisition of expression of switched isotypes or differentiation to plasma-like cells capable of secreting all major Ig isotypes. The B cells that had undergone switching to become IgG⁺ or IgA⁺ were distinct from those that committed to a plasma cell fate – thus, the secreted Ig detected in these cultures was derived from the in vitro-derived plasma cells rather than the surface IgG⁺/IgA⁺ class switched cells. Both class switching and plasma cell formation induced by IL-21 could be modulated by additional cytokines, such as IL-4 (promoted switching to IgG; inhibited switching to IgA; increased secretion of IgG and IgE; suppressed secretion of IgM, IgA), IL-10 (increased IgA secretion), and IL-2 (increased secretion of IgM, IgG). These differentiation events coincided with the induction in expression of BCL-6, AICDA (required for class switching), and BLIMP-1/XBP-1 (required for plasma cell formation). The ability of IL-21 to induce naïve B cells to differentiate into plasmablasts/plasma cells in vitro was abolished by hypomorphic mutations in STAT3, as well as null mutations in IL21R or IL2RG.