Long-term protective immunity to infectious disease depends on cell-mediated and humoral immune responses. Induction of a strong humoral response relies on efficient B cell activation and differentiation to long-lived plasma cells and memory B cells. For many viral or bacterial infections, a single encounter is sufficient to induce such responses. In malaria, the induction of long-term immunity can take years of pathogen exposure to develop, if it occurs at all. This repeated pathogen exposure and suboptimal immune response coincide with the expansion of a subset of B cells, often termed atypical memory B cells. This subset is present at low levels in healthy individuals as well but it is observed to expand in an inflammatory context during acute and chronic infection, autoimmune diseases or certain immunodeficiencies. Therefore, it has been proposed that this subset is exhausted, dysfunctional, or potentially autoreactive, but its actual role has remained elusive. Recent reports have provided new information regarding both heterogeneity and expansion of these cells, in addition to indications on their potential role during normal immune responses to infection or vaccination. These new insights encourage us to rethink how and why they are generated and better understand their role in our complex immune system. In this review, we will focus on recent advances in our understanding of these enigmatic cells and highlight the remaining gaps that need to be filled.

CD11c, FcRL5, or T-bet are commonly expressed by B cells expanding during inflammation, where they can make up >30% of mature B cells. However, the association between the proteins and differentiation and function in the host response remain largely unclear. We have assessed the co-expression of CD11c, T-bet and FcRL5 over one year in patients treated for malaria. We observed dynamic co-expression profiles that changed over time, suggesting ongoing differentiation. We used an in vitro B cell culture system to determine how stimulation via the B cell receptor (BCR), toll-like receptor 9 (TLR9), and different cytokines could influence CD11c, T-bet, and FcRL5 expression. We observed different expression dynamics for all markers, but a largely overlapping regulation of CD11c and FcRL5 in response to BCR and TLR9 activation, while T-bet was strongly dependent on IFN-γ signalling. Investigating plasma cell differentiation and antigen-presenting cell functions, there was no association between marker expression and antibody secretion or T cell help, although the functions were associated with TLR9-signalling and B cell-derived IL-6 production, respectively. These results point to CD11c, FcRL5, and T-bet expression representing different activation stages and highlight the value of using multiple markers when assessing B cell differentiation.