Figure 7.

Schematic diagram of interaction between T follicular helper (Tfh) and B cells initiating synergetic effect of IL-21/IL-21R and CD40 ligand (CD40L)/CD40 to promote plasma cell differentiation and antibody production in EAE. (A) The process of antigen-activated T cells and B cells migrating to the B cell follicles, where enables B cells receive helper signals from Tfh cells. Red pentacle cells stand for dentritic cells and green pentacle ones for follicular dentritic cells. (B) At the T-B border, B cells receive signals from cognate CD4⁺ T cells to activate and proliferate. (C) Within the germinal centers (GCs), MOG-specific B cells recognize antigen and present it to Tfh cells. After receiving activation signal of MHC-peptide complex and ICOSL from B cells, Tfh cells secret large amount of IL-21 and express CD40L. IL-21 and CD40L bind to the relevant receptor and ligand on B cells, respectively. The ligation of CD40L and CD40 promote the stabilization of NF-κB-inducing kinase (NIK), and activate the downstream pathway, which lead the formation of P52 and initiate the expression of B lymphocyte-induced maturation protein-1 (Blimp-1). IL-21 receptor activates the JAK/STAT3 pathway and phosphorylated STAT3 (p-STAT3) promotes the expression of Blimp-1. Moreover, P-STAT3 could also upregulate the expression of NIK, probably through stimulating the de novo synthesis of NIK (red thin arrow). Thus, the signal provided by IL-21 and CD40L synergistically facilitates the differentiation of B cells and autoantibody production.