Follicular CD4+ T helper cells induce human B cells to undergo Ig isotype switching and differentiation to Ig-secreting cells through the production of IL-21 (95.1)

Abstract The primary function of B cells is to produce high-affinity Ag-specific Ig by differentiating into plasma cells. Naïve B cells can also alter the effector function of their Ig molecule by class switch recombination (CSR). CSR and plasma cell differentiation occur within germinal centres (GC) and are believed to be largely regulated by signals delivered by T follicular helper (TFH) cells. TFH cells reside within the GC and can be resolved from other T-cell populations by the expression of elevated levels of CXCR5. The mechanism by which TFH cells induce B-cell differentiation is unknown. We examined the effects of IL-21, a product of TFH cells, as well as these cells themselves, on the fate of human naïve B cells. IL-21 induced CD40L-stimulated naïve B cells to undergo CSR to acquire expression of IgG and IgA, and secrete large amounts of IgG, IgA and IgE. Isotype switching induced in CD40L-stimulated naïve B cells by IL-21 was linked to cell division, as revealed by analysis of CFSE-labelled B cells. The addition of IL-4 to cultures of CD40L/IL-21-stimulated naïve B cells had divergent and isotype-specific effects with IL-4 enhancing IL-21-induced switching to IgG and IgE whilst inhibiting switching to IgA. When naïve B cells were co-cultured with autologous tonsillar TFH cells, but not CD4+CXCR5− T cells, they produced high levels of IgM, IgG and IgA. Strikingly, differentiation of autologous naïve B cells by TFH cells was abrogated by neutralising endogenous IL-21. These findings demonstrate the critical role of IL-21 in TFH-cell dependent B-cell differentiation and suggest that diminished or excessive production of IL-21 may contribute to the development of immunodeficiencies or autoimmune diseases, respectively.