Plasmodium-specific atypical memory B cells are short-lived activated B cells
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ABSTRACT:
PROVIDER: PRJNA473982 | ENA |
REPOSITORIES: ENA
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Project description:Chronic infections such as HIV, tuberculosis and malaria in humans are associated with the appearance of atypical memory B cells in peripheral blood. It has been suggested that these B cells do not function normally as memory cells, and thus may be responsible for poor acquisition of immunity and maintenance of chronic infections. Studies on these cells in human infections are limited by the lack of accessibility to lymphoid organs, and relevant mouse models would be valuable to investigate their development, functional capacities, and role. To investigate Plasmodium-specific memory B-cell responses during malaria, we generated an immunoglobin heavy chain knock-in mouse with a B-cell receptor that recognizes the merozoite surface protein (MSP)-1 of the rodent malaria parasite, Plasmodium chabaudi. Using this mouse and a P. chabaudi infection initiated by infected mosquito bites we show that antigen-specific B cells with many characteristics of human atypical memory B cells are generated. These cells are immunoglobulin class-switched and express, among others, the cell surface molecules CD11c, CD11b, FCRL5, and some inhibitory receptors including PD1 and LAIR-1, as well as the transcription factor T-bet. Antigen-specific atypical memory B cells are detected side-by-side with classical memory B cells during chronic blood-stage infection. Whereas classical memory B cells persist after complete infection clearance, atypical memory B cells are short-lived and disappear from the spleen at the resolution of chronic infection. Short-lived Plasmodium-specific atypical B cells also appear transiently after immunization with a TLR7/8 ligand and MSP-1. Our data suggest that these atypical memory B cells are not a subset of memory B cells, but rather antigen-experienced activated cells, and part of a normal ongoing response. Their persistence over weeks in malaria and other infections may be a consequence of continued and chronic antigenic stimulation.
2018-11-01 | GSE115155 | GEO
Project description:CD8 effector T cells with a CD127hi KLRG1- phenotype are considered precursors to the long-lived memory pool, while KLRG1+ CD127low cells are viewed as short-lived effectors. Nevertheless, we and others have shown that a KLRG1+ CD127low population persists into the memory phase and that these T cells (termed long-lived effector cells or LLEC) display robust protective function during acute re-challenge with bacteria or viruses. Whether these T cells represent a true memory population or are instead a remnant effector cell population that failed to undergo initial contraction has remained unclear. Here, we show that LLEC from mice express a distinct phenotypic and transcriptional signature that shares characteristics of both early effectors and long-lived memory cells. Furthermore, we find that LLEC are exclusively derived from day 12 KLRG1+ effector cells. Our work challenges the concept that the KLRG1+ CD127low population is dominated by short-lived cells and shows that KLRG1 downregulation is not a prerequisite to become a long-lived protective memory T cell.
2020-08-26 | GSE152841 | GEO
Project description:KLRG1+ Memory CD8 T cells Combine Properties of Short-lived Effectors and Long-lived Memory
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Project description:Rapid protein degradation enables cells to quickly modulate protein abundance in response to stimuli. Previous studies have generally sought to delineate basic features of proteome turnover. A focused map of short-lived proteins, however, remains a missing piece of the human proteome. To begin to address this, we combined cycloheximide chase assays with advanced high-throughput quantitative proteomics to map short-lived proteins in four genetically distinct human cell lines. Apparent half-lives of ≤ 8 hr were measured for 1,017 proteins. Systematic analyses revealed general properties of short-lived proteins (e.g., enriched in substrate recognition subunits of E3 ubiquitin ligase complexes, thermally instable, evolutionarily younger). We further quantified 103 proteins with widely different stabilities among cell lines. Of these, we show that truncated forms of ATRX and GMDS were expressed in U2OS and HCT116 cells, respectively, which had shorter half-lives than their full-length counterparts. This study provides a large-scale resource of human short-lived proteins in cultured cells, leading to untapped avenues of protein regulation for therapeutic intervention.
2022-02-07 | PXD024513 | Pride
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| S-EPMC6242553 | biostudies-literature
Project description:Plasmodium falciparum malaria is a deadly infectious disease for which we have no licensed vaccine. Antibodies confer protection against malaria and individuals exposed to P. falciparum acquire protective antibodies, but only after years of repeated infections. We recently showed that malaria exposure is associated with a large expansion of a population of atypical memory B cells (MBCs) that phenotypically resemble B cell populations expanded in chronic viral infections, including HIV. At present the relationship of atypical MBCs to classical MBCs and their function are not known. We provide evidence that the expressed VH gene repertoires and somatic hypermutation rates of atypical and classical MBCs are indistinguishable, indicating the two populations are closely related developmentally. Atypical MBCs can be distinguished by their expression of multiple inhibitory receptors, including Fc receptor-like-5. B cell receptor (BCR) signaling is stunted in atypical MBCs, resulting in impaired Ca2+ mobilization, proliferation and cytokine production. Atypical MBCs do not spontaneously secrete antibodies and cannot be stimulated to differentiate into antibody-secreting cells in vitro. These results suggest that in individuals chronically exposed to malaria, atypical MBCs differentiate from classical MBCs and assume a phenotype refractory to BCR-mediated activation, potentially contributing to the inefficient acquisition of immunity to malaria. Comparison of human atypical B cell versus classical B cell versus naïve B cell.
2015-05-07 | E-GEOD-65928 | biostudies-arrayexpress
Project description:Plasmodium falciparum malaria is a deadly infectious disease for which we have no licensed vaccine. Antibodies confer protection against malaria and individuals exposed to P. falciparum acquire protective antibodies, but only after years of repeated infections. We recently showed that malaria exposure is associated with a large expansion of a population of atypical memory B cells (MBCs) that phenotypically resemble B cell populations expanded in chronic viral infections, including HIV. At present the relationship of atypical MBCs to classical MBCs and their function are not known. We provide evidence that the expressed VH gene repertoires and somatic hypermutation rates of atypical and classical MBCs are indistinguishable, indicating the two populations are closely related developmentally. Atypical MBCs can be distinguished by their expression of multiple inhibitory receptors, including Fc receptor-like-5. B cell receptor (BCR) signaling is stunted in atypical MBCs, resulting in impaired Ca2+ mobilization, proliferation and cytokine production. Atypical MBCs do not spontaneously secrete antibodies and cannot be stimulated to differentiate into antibody-secreting cells in vitro. These results suggest that in individuals chronically exposed to malaria, atypical MBCs differentiate from classical MBCs and assume a phenotype refractory to BCR-mediated activation, potentially contributing to the inefficient acquisition of immunity to malaria.
2015-05-07 | GSE65928 | GEO
Project description:Atypical B cells are a population of activated B cells that are commonly enriched in individuals with chronic immune activation, but are also part of a normal immune response to infection or vaccination. Prior studies to determine the function of these cells have yielded conflicting results, possibly due to functional heterogeneity among this B cell population. To better define the role(s) of atypical B cells in the host adaptive immune response, we performed single-cell sequencing of transcriptomes, cell surface markers, and B cell receptors in individuals with chronic Plasmodium falciparum exposure, a condition known to lead to accumulation of circulating atypical B cells. Our studies identified three previously uncharacterized populations of atypical B cells with distinct transcriptional and functional profiles, that separate into two differentiation pathways. We identified a set of cell surface markers to distinguish these atypical B cell subsets and confirmed their presence in malaria-experienced children and adults using flow cytometry. Plasmodium falciparum-specific cells were present in equal proportions within each of these atypical B cell populations, indicating that all three subsets develop in response to antigen stimulation. However, we observed marked differences among the three subsets in their ability to produce IgG upon T-cell-dependent activation. Collectively, our findings help explain the conflicting observations in prior studies on the functions of atypical B cells and provide a better understanding of their role in the adaptive immune response in chronic inflammatory conditions.
2023-12-22 | GSE235824 | GEO
Project description:Comparison of long-lived daf-2 pathway mutants with wild type/short-lived mutants. A: age-1 fer-15; fem-1 vs. fer-15; fem-1. B: age-1 fer-15; fem-1 vs. fer-15; fem-1. C: fer-15; daf-2(mu150); fem-1 vs. fer-15; fem-1. D: fer-15; daf-2(mu150); fem-1 vs. fer-15; fem-1. E: daf-16::gfp in daf-16(mu86);daf-2(e1370) vs. daf-16(mu86);daf-2(e1370). F: daf-2(e1368); fer-15; fem-1 vs. fer-15; fem-1. G: fer-15; daf-2(mu150); fem-1 vs. fer-15; fem-1. H: age-1 fer-15; fem-1 vs. fer-15; fem-1. I: fer-15; daf-2(mu150); fem-1 vs. fer-15; fem-1. J: daf-16::gfp in daf-2(e1370); daf-16(mu86) vs. daf-2(e1370); daf-16(mu86). K: daf-2(mu150) vs. wild type. L: daf-2(e1370) vs. daf-2(e1370); daf-16(mu86). M: daf-2(e1370) vs. daf-2(e1370); daf-16(mu86). N: daf-2(e1370) vs. daf-2(e1370); daf-16(mu86).
2003-07-17 | E-MEXP-7 | biostudies-arrayexpress
Project description:Effector CD8 T cells dedifferentiate into long-lived memory cells
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