T follicular helper (T FH ) cells are a specialized subset of CD4 + T cells that localize to B-cell follicles, where they are positioned to provide help for the induction of optimal humoral immune responses. Key features of T FH cells are the expressions of CXCR5, ICOS, interleukin (IL)-21 and BCL-6. The requirements for human T FH cell development are unknown. Here we show that IL-6, IL-12, IL-21 and IL-23 are capable of inducing IL-21 expression in naïve CD4 + T cells isolated from human tonsils, peripheral blood and cord blood. However, only IL-12 induced sustained expressions of CXCR5 and ICOS on these activated naïve CD4 + T cells, and endowed them with the ability to provide increased help to B cells for their differentiation into immunoglobulinsecreting cells. The effects of IL-12 were independent of interferon-c and T-bet, and associated with upregulation of BCL-6 expression. Thus, these cytokines, particularly IL-12, are likely to act at an early stage during dendritic cell-mediated priming of naïve CD4 + T cells into a T FH cell fate, and thus underpin antibody-mediated immunity.
Summary
Effective humoral immunity depends on the support of B cell responses by T-follicular helper (Tfh) cells. Whilst it has been proposed that Tfh cell differentiation requires T-B interactions, the relative contribution of specific populations of Ag presenting cells remains unknown. We employed three independent strategies that compromised interactions between CD4+ T cells and activated B cells in vivo. Whereas the expansion of CD4+ T cells was relatively unaffected, Tfh cell differentiation was completely blocked in all scenarios. Surprisingly, augmenting antigen presentation by non-B cells rescued Tfh cell differentiation, as determined by surface phenotype, gene expression and germinal center localization. We conclude that although Ag presentation by responding B cells is typically required for the generation of Tfh cells, this does not result from the provision of a unique B cell-derived signal, but rather because responding B cells rapidly become the primary source of antigen.
Memory B cells, unlike naive B cells, require a reduced level of STAT3 activation to differentiate into antibody-secreting plasmablasts in response to IL-10 and IL-21; however, this process requires IL-21R expression in both naive and memory cells.
Analysis of females carriers of the X-linked lymphoproliferative (XLP) trait reveals the mechanism underlying exquisite sensitivity of XLP patients to often-fatal infection with the normally innocuous Epstein-Barr virus.
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