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

Damián Pérez-Mazliah,Victor Lj Tybulewicz,Edina Schweighoffer,Jean Langhorne,Alexandre J Potocnik,Randall S Davis,Peter J Gardner,Sarah Mclaughlin,Caroline Hosking,Irene Tumwine

doi:10.7554/elife.39800

Damián Pérez-Mazliah, Victor Lj Tybulewicz + Show 8 more

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https://doi.org/10.7554/elife.39800

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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.

Highlights

Atypical memory B cells (AMB) are an unusual B-cell subset detected in both mouse models and humans in the context of certain infections and autoimmune disorders, including HIV, HCV, tuberculosis, malaria, rheumatoid arthritis and systemic lupus erythematosus, and accumulated with age (Knox et al, 2017b; Naradikian et al, 2016a; Portugal et al, 2017; Rubtsov et al, 2017)
There were no alterations in total cellularity, pro-B, pre-B, immature B, mature B, total B220+CD19+ B cells, and plasma cells in the bone marrow (Figure 1A–B), and no alterations in number of T1, T2, T3, follicular, marginal zone, germinal center B cells, plasmablasts, plasma cells, and total cellularity in the spleen of IghNIMP23/+ mice (Figure 1C–D) (Sen et al, 1990; Young et al, 1994)
We have generated an IgH knock-in transgenic mouse strain to study the generation of Plasmodium-specific AMB in a Plasmodium chabaudi infection

Summary

Introduction

Atypical memory B cells (AMB) are an unusual B-cell subset detected in both mouse models and humans in the context of certain infections and autoimmune disorders, including HIV, HCV, tuberculosis, malaria, rheumatoid arthritis and systemic lupus erythematosus, and accumulated with age (Knox et al, 2017b; Naradikian et al, 2016a; Portugal et al, 2017; Rubtsov et al, 2017). In addition to FCRL4, these cells express relatively high levels of other potentially inhibitory receptors including CD22, CD85j, CD85k, LAIR-1, CD72, and PD-1, and show a profile of trafficking receptors including expression of CD11b, CD11c and CXCR3, consistent with migration to inflamed tissues. They are antigen-experienced classswitched B cells, which lack the expression of CD21 and the hallmark human memory B-cell marker CD27. Due to their poor functional capacity upon in vitro re-stimulation with BCR ligands, AMB were characterized as dysfunctional B cells, and increased frequencies of these cells was proposed to be a consequence of B-cell exhaustion driven by chronic inflammation and stimulation, drawing parallels with T-cell exhaustion during chronic viral infections

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