Plasmodium-specific atypical memory B cells are short-lived activated B cells

Abstract

A subset of atypical memory B cells accumulates in malaria and several infections, autoimmune disorders and aging in both humans and mice. It has been suggested these cells are exhausted long-lived memory B cells, and their accumulation may contribute to poor acquisition of long-lasting immunity to certain chronic infections, such as malaria and HIV. Here, we generated an immunoglobulin heavy chain knock-in mouse with a BCR that recognizes MSP1 of the rodent malaria parasite, Plasmodium chabaudi. In combination with a mosquito-initiated P. chabaudi infection, we show that Plasmodium-specific atypical memory B cells are short-lived and disappear upon natural resolution of chronic infection. These cells show features of activation, proliferation, DNA replication, and plasmablasts. Our data demonstrate that Plasmodium-specific atypical memory B cells are not a subset of long-lived memory B cells, but rather short-lived activated cells, and part of a physiologic ongoing B-cell response.

FCRL5+ Memory B Cells Exhibit Robust Recall Responses

“…Comparisons with existing meta-analyses that assess the similarity of tissue-specific gene signatures between mice and humans (e.g., Zheng-Bradley et al, 2010 ) suggest that this level of transcriptional similarity likely does imply biological similarity between the cell subsets. In further support of this conclusion, a recent study that performed transcriptional profiling on Plasmodium -specific transgenic B cells in mice infected with P. chabaudi also found evidence for a relationship between murine cells expressing atypical markers and human atMBCs ( Pérez-Mazliah et al, 2018 ).…”

“…Both markers were elevated on FCRL5 + OVA-specific and GP-specific cells elicited by protein immunization and LCMV expression, respectively ( Figure S5 ), but expression was reduced compared to a similar time point after Plasmodium infection ( Figure 7C ). It seems likely that CD11b and CD11c are more transiently ex- pressed following immunization and even acute viral infection compared to P. chabaudi infection, in which parasites persist for months; in keeping with this, Pérez-Mazliah et al (2018) report that injection of MSP1 protein with a Toll-like receptor 7/8 (TLR7/8) ligand elicits a transient population of CD11b + CD11c + antigen-specific B cells that peaks 24 h post-immunization. Together with observations from P. chabaudi , these data suggest that some atypical markers diminish over time, and that their expression intensity correlates with recency of activation.…”

“…We examined the expression of FCRL5 on various antigen-specific B cell subsets. In a recent study, transcriptional profiling led the authors to suggest that FCRL5 + MSP1-specific B cells expressed a plasmablast- or pre-plasmablast-like signature, but cell surface markers for plasmablasts were not assessed ( Pérez- Mazliah et al, 2018 ). Therefore, we examined antigen-specific B cells for expression of these and other subset markers.…”

“…Because several markers expressed on human atMBCs are broadly associated with B cell activation (e.g., CD80, CD86, and CD11c), a key question is whether the atypical phenotype represents a stable cellular identity or rather a transient activation state. In their study of BCR-transgenic mice infected with P. chabaudi , Pérez-Mazliah et al (2018) show that many MSP1-specific B cells robustly express atypical markers 35 d.p.i., a time when parasites are still present; our data from day 28 replicate these findings ( Figure 3H ). In contrast, they report that at day 155, several months after the infection has been cleared, antigen-specific MBCs express FCRL5 but not the other markers examined (CD11b, CD11c, and T-bet).…”

Impact of BAFF Blockade on Inflammation, Germinal Center Reaction and Effector B-Cells During Acute SIV Infection

“…Rapid loss in AM B-cells at the acute phase of infection predicts accelerated progression toward the chronic phase (11). First considered as exhausted B-cells due to the expression of FcRL5/4 and PD1 (12), TLM B-cells are now thought to be short-lived, early plasma blasts or recent GC emigrants that are maintained by repetitive antigen exposure during chronic infection but also physiologically during vaccination (13). Both TLM and AM highly express FcRL4 and overproduce IL6 in chronically HIV-infected individuals, with FcRL4 hi IL6 hi AM acting as potent pro-inflammatory B-cells (14).…”