Potential functions of atypical memory B cells in Plasmodium-exposed individuals

Abstract

Naturally acquired iummunity against clinical malaria is slow to develop, taking years of repeated exposure to parasites to acquire sufficiently broad and potent antibody responses. Increasing evidence suggests that Plasmodium infection and the resulting immune stimulation contribute to changes in the B cell compartment. In particular, accumulation of atypical memory B cells (atMBCs) is common in Plasmodium-exposed individuals. Similarities to B cell subsets present in other acute and chronic disease settings have provided insight into the development and potential function of these cells; however, their contribution to protection against malaria is still poorly understood. Here, we discuss recent findings that have increased our understanding of atMBCs and outline outstanding questions related to their function and development in the protective immune response to malaria.

Keywords: Atypical memory B cell; FcRL5; Humoral immunity; IFNγ; Plasmodium; T-bet.

Fig. 1.

Potential pathways of atypical memory B cell (atMBC) development. In response to Plasmodium infection, antigen-recognising naïve B cells interact with antigen through B cell receptors (BCRs) and receive survival signals from CD4⁺ T cells, which drive naïve B cells to enter germinal centres (GCs) (1). In the GC, these B cells undergo proliferation and somatically hypermutate the BCR to increase antigen affinity (2). In the light zone of the GC, B cells with high affinity are selected through interactions with antigen-presenting follicular dendritic cells and CD4⁺ T follicular helper (Tfh) cells before undergoing class switch recombination (3). Poor Tfh cell help during this step may drive B cell differentiation into atMBCs (4). B cells can undergo multiple rounds of affinity maturation (5) before exiting the GC. Outside of the GC, B cells can differentiate into plasma cells (6) which produce high affinity antibodies to control the infection, or differentiate into long-lived memory B cells (7) which remain in circulation to respond to subsequent infections. Upregulation of inhibitory receptors and reduced BCR signalling driven by poorly understood mechanisms may promote the development of atMBCs from classical MBCs (8), representing an abnormal immune response. Alternatively, atMBCs could arise during activation of MBCs in a normal response to infection via an unknown mechanism (9). Finally, similar to DN2 cells in lupus, atMBCs may represent a population of pre-antibody secreting cells originating from the extra-follicular activation of naïve B cells (10).

Fig. 2.

Potential drivers of the atypical memory B cell (atMBC) phenotype in response to Plasmodium infection. Plasmodium infection activates the immune system in several distinct, yet complimentary, ways which seem to promote the development of atMBCs. Infected erythrocytes stimulate increased IFNγ production by innate immune cells (1). High serum levels of IFNγ promote the development of Th-1 polarised T follicular helper (Tfh-1) cells which provide poor B cell help during germinal centre reactions (2). In response to infected erythrocytes, dendritic cells undergo a unique activation programme (3) also resulting in the promotion of Th-1 polarised Tfh-1 cells (4). Crosslinking of the B cell receptor (BCR) by antigen (5) and activation of Toll-like receptor-9 (TLR9) by Plasmodium DNA (6) both contribute to the upregulation of transcription factor T-bet, impaired BCR signalling, and development of an atypical phenotype. T-bet expression in B cells can also be induced by IFNγ signalling through the IFNγ receptor (IFNγ-R) (7).