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

Abstract

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 malaria-exposed 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 naïve B cells that was abrogated by neutralizing IFN-γ or blocking the IFN-γ receptor on B cells. Accordingly, recombinant IFN-γ 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 naïve B cells. These data provide new insight into the mechanisms underlying atypical MBC differentiation. Antibodies are proteins in blood that help kill microbes such as viruses, bacteria and parasites. Antibodies are produced by B cells with the help of T follicular helper (Tfh) cells. Some microbes for which we have no effective vaccines, such as HIV and malaria, establish chronic infections that are not cleared by the immune system. These chronic infections are associated with ‘atypical’ B cells that are less able to produce antibodies. We studied blood samples of malaria-exposed children to understand why normal B cells become atypical B cells. We found that atypical B cells express high levels of T-bet—a protein that is important for determining the fate of other types of immune cells. Children who frequently got malaria had more T-bet expressing B cells than children who rarely got malaria. We also found that malaria parasites cause immune cells to secrete inflammatory substances that cause normal B cells to express T-bet. Similarly, the inflammation-prone Tfh cells that malaria activates, which are relatively poor B cell helpers, also caused normal B cells to express T-bet. This study helps us understand why atypical B cells arise during chronic infections—information that could lead to strategies to improve antibody responses through vaccination.