IL-21 neutralizing antibody inhibits human T-FH proliferation and T-FH-mediated maturation of naive B cells

The hallmark of T follicular helper (T FH ) cells is the ability to help B cells generate humoral immune responses. Recent evidence suggests that aberrant function of T FH cells plays a key role in the generation of autoantibodies, which can inflict autoimmune pathologies. T FH cells are characterized by their unique master regulator (Bcl6), surface marker expression (CXCR5 and ICOS), and production of the pro-inflammatory cytokine interleukin-21 (IL-21). In mice, IL-21 is described as a regulator of T FH cell differentiation and B cell maturation, but its role in human T FH cells remains incompletely understood. In the present study, we sorted T FH subsets from human tonsils or T FH -like cells from human blood to characterize IL-21 production and the functional consequences of blocking IL-21 with a neutralizing antibody. IL-21 was highest in T FH HI cells (CXCR5 ++ ICOS ++ ), detectable in T FH INT cells (CXCR5 + ICOS + ), and minimal in non-T FH cells. Anti-IL-21 caused a moderate decrease in anti-CD3 stimulated T FH proliferation. Peripheral CXCR5 + T FH -like cells also had elevated IL-21 production, but anti-IL-21 had little effect on T FH -like proliferation. When T FH INT, T FH HI, or T FH -like cells were co-incubated with naive B cells, anti-IL-21 decreased B cell maturation and Ig production in a dose-dependent manner. Together, these findings indicate that anti-IL-21 inhibits T FH generation and B cell help, and is a promising therapeutic for autoimmune disorders involving autoantibody production.