Malaria-induced interferon-γ drives the expansion of Tbet hi atypical memory B cells

Many chronic infections, including malaria and HIV, are associated with a large expansion of CD21(-)CD27(-)'atypical' memory B cells (MBCs) that exhibit reduced B cell receptor (BCR) signaling and effector functions. Little is known about the conditions or transcriptional regulators driving atypical MBC differentiation. Here we show that atypical MBCs in malariaexposed individuals highly express the transcription factor T-bet, and that T-bet expression correlates inversely with BCR signaling and skews toward IgG3 class switching. Moreover, a longitudinal analysis of a subset of children suggested a correlation between the incidence of febrile malaria and the expansion of T-bet hi B cells. The Th1-cytokine containing supernatants of malaria-stimulated PBMCs plus BCR cross linking induced T-bet expression in naive B cells that was abrogated by neutralizing IFN-gamma or blocking the IFN-gamma receptor on B cells. Accordingly, recombinant IFN-gamma plus BCR cross-linking drove T-bet expression in peripheral and tonsillar B cells. Consistent with this, Th1-polarized Tfh (Tfh-1) cells more efficiently induced T-bet expression in naive B cells. These data provide new insight into the mechanisms underlying atypical MBC differentiation.