Differential requirement for STAT3 in regulating human B cell differentiation. Naive B cells can be induced to undergo proliferation, isotype switching, and differentiation to the PC lineage via distinct pathways: (A) in vitro in response to TD stimulation (CD40L plus IL-21), (B) in vivo in response to TD Ag and subsequent GC formation, and (C) in response to TD and T cell–independent stimuli in the form of CD40L and/or BAFF, APRIL, TLR ligands (e.g., viral double-stranded RNA [TLR3] or CpG [TLR9]), and cytokines. Mutations in STAT3 differentially affect each of these pathways (red text). By impairing the up-regulation of PRDM1 (BLIMP-1) and XBP1, STAT3_MUT B cells are unable to become ISCs in vitro; in contrast, induction of AICDA and Ig isotype switching are intact (A). Although GCs can be detected in STAT3_MUT patients, the output of memory B cells and efficient PCs, as assessed by reduced numbers of CD27+ B cells and serum Ab titers against specific Ag, respectively, is impaired. This may result from reduced induction of BCL6 in response to IL-21. Ig production by STAT3_MUT B cells in response to STAT3-independent TD and T cell–independent pathways is intact; this may explain the normal serum Ig levels in these patients (C).