Alternative B Cell Differentiation During Infection and Inflammation

Abstract

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.

Keywords: CD11c; CD21; FcRL5; T-bet; atypical memory B cells; double-negative B cells; tissue-like B cells.

Figure 1

Kinetics of CD21^lo CD11c⁺ T-bet⁺ B cells during acute and chronic disease. (A) Under specific conditions such as B cell receptor (BCR) activation in the presence of IFN-γ and T cell help, B cell will acquire a phenotype characterized by reduced expression of CD21 and increased expression of CD11c (ITGAX), T-bet (TBX21) and FCRL4/5. (B) They then rapidly expand over several weeks until they start to contract over several months in the absence of antigen (red line). In the context of chronic infection or repeated infection (blue line), the cells can remain a substantial proportion of total B cells until treatment removes the source of antigen and reduce the inflammatory response.

Figure 2

CD21^lo B cell responsiveness is dependent on how antigen is presented. CD21^lo B cells expressing CD11c, T-bet (TBX21), and FCRL5 also express increased levels of inhibitory receptors, such as FcγRIIB. In the context of B cell receptor (BCR) ligation, FcγRIIB reduces the engagement of CD19 with the BCR, thus preventing down stream signaling, leading to hyporesponsiveness. In contrast, CD21^lo B cells binding to membrane arrayed antigens establish an immunological synaps that excludes FcγRIIB. This allows CD19 to engage the BCR and promote downstream signaling, leading to transcription of IRF4 that in turn can drive differentiation to antibody secreting cells. The membrane-arrayed antigens also lead to improved antigen-uptake and could potentially enhance the B cell antigen-presenting cell functions.