The interplay of IL-21 and BAFF in the formation and maintenance of human B cell memory

To date, 11521 stands out as the most influential cytokine for human B cell activation and differentiation. Indeed, when compared to other important B cell tropic cytokines such as 11,2, 11,4, 11,6 and 11,10, 11521 is clearly the most potent in terms of its ability to influence humoral immune responses in humans. IL21 has wide reaching actions in determining how B cells will respond to co-stimulation ranging from induction of cell death upon BCR crosslinking to potent induction of class switch recombination and plasma cell differentiation when CD40 molecules are co-engaged. Another crucial B cell factor, exemplified in recent clinical trials, is BAFF/BLys. BAFF plays a critical role in the survival of human B cells and plasma blasts and influences B cell expansion and migration. Recent evidence has shown that IL21 and BAFF can work in concert to promote and perhaps maintain humoral immunity in humans. Notably, BAFF has the unique ability to substitute for CD4OL activities in regard to IL21-co-stimulation and differentiation of a specific B cell subpopulation located in the human splenic marginal zone. However, and perhaps surprisingly, BAFF signals do not have the capability to override IL-21-driven cell death events when BCR is engaged. In stark contrast, anti-CD40 ligation of B cells co-activated with IL21 and anti-IgM not only reverses this aforementioned activation-induced cell death, but transforms this death signal into one that drives plasma cell differentiation. Here we will discuss these two critical B cell factors, IL21 and BAFF, and their distinct and complimentary effects on human B cell responses.