Evidence that Th1-polarized Tfh cells drive the differentiation of T-bethi atypical memory B cell expansion in human malaria

Abstract

Abstract Many chronic infections, including malaria and HIV, are associated with a large expansion of CD21−CD27−CXCR3+CD11c+ ‘atypical’ memory B cells (MBCs) that exhibit reduced effector functions. Little is known about the conditions or transcriptional regulators driving atypical MBC differentiation. Here we show that atypical MBCs in malaria-exposed individuals highly express the transcription factor T-bet. Moreover, a longitudinal study of malaria-exposed children demonstrated a positive correlation between the incidence of febrile malaria and the expansion of T-bethi B cells. The Th1-cytokine containing supernatants of malaria-stimulated PBMCs and B cell receptor (BCR) cross- linking induced T-bet expression in peripheral and tonsilar B cells that were blocked by neutralizing IFN-γ. Accordingly, recombinant IFN-γ plus BCR cross-linking drove T-bet expression in peripheral and tonsilar B cells. Consistent with this, Th1-polarized Tfh (Tfh-1) cells more efficiently induced T-bet expression in naïve B cells. These data illuminate the mechanisms underlying atypical MBC differentiation.