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Limited access to antigen drives the generation of early B cell memory while restraining the plasmablast response

ABSTRACT: The cell fate decisions between plasmablasts (PBs), germinal center B cells (GCBCs) and non-GC-derived memory B cells (MBCs) during early B cell activation determine the outcome of the immune responses to pathogens and vaccines. In this study, we dissected these poorly characterized lineage choices by single-cell RNA-sequencing. Early after immunization, a homogenous population of activated precursors (APs) gave rise to a transient wave of PBs, followed a day later by the emergence of the first GCBCs, with the transcriptomes of both rapidly diverging from that of APs. The majority of APs started to withdraw from the cell cycle very early on and gave rise to GC-independent MBCs, a developmental transition that involved limited transcriptional changes. These events were controlled by antigen availability, and provision of antigen excess interfered with cell cycle exit and induced a new wave of PBs. Fate mapping experiments revealed a prominent contribution of GC-independent memory to the overall MBC pool. Quiescent cells with an MBC phenotype also dominated the early response to immunization in primates, indicating evolutionary conservation. Thus, excess APs, kept in reserve as early MBCs, can be rapidly re-recruited if failure to contain a threat is manifested by increased antigen availability, thus providing a feedback mechanism for rapid readjustment of the immune response.

ORGANISM(S): Mus musculus

PROVIDER: GSE175427 | GEO | 2021/08/19

REPOSITORIES: GEO

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Project description:The cell fate decisions between plasmablasts (PBs), germinal center B cells (GCBCs) and non-GC-derived early memory B cells (eMBCs) during early B cell activation determine the outcome of the immune responses to pathogens and vaccines. To characterize these poorly understood lineage choices, we dissected the early B cell responses to T-dependent antigen in mice by single-cell RNA-sequencing. Early after immunization, a homogenous population of activated precursors (APs) gave rise to a transient wave of PBs, followed a day later by the emergence of the first GCBCs, with the transcriptomes of both rapidly diverging from that of APs. The majority of APs started to withdraw from the cell cycle very early on and gave rise to eMBCs, a developmental transition that involved limited transcriptional changes. These events were controlled by antigen availability that rapidly declined soon after immunization, and provision of antigen excess interfered with the cell cycle exit of APs and induced a new wave of PBs. Fate mapping experiments revealed a prominent contribution of eMBCs to the overall MBC pool. Generation of the earliest GCBCs was tightly controlled by the transcriptional repressor Bhlhe40 in the absence of which this population was increased in numbers. Bhlhe40 also restrained in a cell intrinsic fashion the response of T follicular helper (TFH) cells, a specialized T helper cell subset required to mount the GC response. In B cells, Bhlhe40 executed its function in the first days after immunization by selectively restricting the generation of the earliest GCBCs but not of eMBCs or PBs. Conditional Bhlhe40 inactivation confirmed cell-autonomous functions of Bhlhe40 in both GCBCs and TFH cells, while the GC phenotype was further enhanced upon loss of Bhlhe40 in both cell types. This negative regulation of the GC reaction by Bhlhe40 was of crucial importance, as Bhlhe40-deficient mice with progressing age succumbed to a B cell lymphoma characterized by the accumulation of monoclonal GCBCs-like cells and polyclonal TFH cells in various tissues.

Project description:Long-term humoral immunity is partly maintained by memory B cells (MBCs). MBCs can be recalled to produce antibody-producing plasma cells (PCs) or form secondary germinal centers (GCs). The former process underlies markedly increased antigen-specific antibodies seen in the secondary response, while the latter process allows continuous somatic hypermutation and affinity maturation. MBC re-participation in the GC reaction is thought to be important for generating broadly neutralizing antibodies against highly mutating viruses such as influenza and HIV. However, how MBC recall is transcriptionally or epigenetically programmed to produce secondary PCs or GCs is not yet understood. Here we show that BACH2, a transcription factor required for GC formation and maintenance1,2, decreases across post-activation stages of B cells, from the NAIVE state to GC, memory, and the terminal PC state. In contrast, BLIMP-1, a transcription factor that promotes PC formation3,4 and is antagonistic to BACH2 (ref. 5), increases as B cells traverse the same course. The relative strength between BLIMP-1 and BACH2 progressively increases in favor of BLIMP-1 in GCs and MBCs through the primary response. MBCs of the isotype or subset identity that preferentially give rise to secondary GCs exhibit comparatively higher BACH2 but lower BLIMP-1 expression than those predisposed for PC formation. Using a tetracycline-controlled circuit implanted in MBCs, we show that skewing the BLIMP-1-BACH2 balance in favor of BACH2 markedly increases GC formation by otherwise PC-predisposed MBCs, whereas skewing the balance in favor of BLIMP-1 drives PC formation by GC-prone MBCs, indicating that the potential for GC re-participation or PC development rests in the relative strength of BLIMP-1 over BACH2 within individual MBCs. Underneath this relative BLIMP-1-over-BACH2 strength in NAIVE B cells, GCs, MBCs and PCs, we observe progressively increased accessibilities to chromatin loci that are specifically opened in PCs, particularly those that contain ISRE elements and are controlled by IRF-4. IRF-4 is universally upregulated in B cells when stimulated through the BCR, the CD40 receptor, or by innate stimuli. By analyzing time-stamped GC B cells, we demonstrate a progressive increase in chromatin accessibilities at PC-specific, IRF-4-controlled gene loci over time. Our results support a model of progressive IRF-4 imprinting in which the cumulative stimulation history of B cells is epigenetically recorded in an IRF-4-dependent manner, determines the relative strength between BLIMP-1 and BACH2 in individual MBCs, and thereby dictates their individual probabilities to develop into GCs or PCs upon re-stimulation.

Project description:Long-term humoral immunity is partly maintained by memory B cells (MBCs). MBCs can be recalled to produce antibody-producing plasma cells (PCs) or form secondary germinal centers (GCs). The former process underlies markedly increased antigen-specific antibodies seen in the secondary response, while the latter process allows continuous somatic hypermutation and affinity maturation. MBC re-participation in the GC reaction is thought to be important for generating broadly neutralizing antibodies against highly mutating viruses such as influenza and HIV. However, how MBC recall is transcriptionally or epigenetically programmed to produce secondary PCs or GCs is not yet understood. Here we show that BACH2, a transcription factor required for GC formation and maintenance1,2, decreases across post-activation stages of B cells, from the naïve state to GC, memory, and the terminal PC state. In contrast, BLIMP-1, a transcription factor that promotes PC formation3,4 and is antagonistic to BACH2 (ref. 5), increases as B cells traverse the same course. The relative strength between BLIMP-1 and BACH2 progressively increases in favor of BLIMP-1 in GCs and MBCs through the primary response. MBCs of the isotype or subset identity that preferentially give rise to secondary GCs exhibit comparatively higher BACH2 but lower BLIMP-1 expression than those predisposed for PC formation. Using a tetracycline-controlled circuit implanted in MBCs, we show that skewing the BLIMP-1-BACH2 balance in favor of BACH2 markedly increases GC formation by otherwise PC-predisposed MBCs, whereas skewing the balance in favor of BLIMP-1 drives PC formation by GC-prone MBCs, indicating that the potential for GC re-participation or PC development rests in the relative strength of BLIMP-1 over BACH2 within individual MBCs. Underneath this relative BLIMP-1-over-BACH2 strength in naïve B cells, GCs, MBCs and PCs, we observe progressively increased accessibilities to chromatin loci that are specifically opened in PCs, particularly those that contain ISRE elements and are controlled by IRF-4. IRF-4 is universally upregulated in B cells when stimulated through the BCR, the CD40 receptor, or by innate stimuli. By analyzing time-stamped GC B cells, we demonstrate a progressive increase in chromatin accessibilities at PC-specific, IRF-4-controlled gene loci over time. Our results support a model of progressive IRF-4 imprinting in which the cumulative stimulation history of B cells is epigenetically recorded in an IRF-4-dependent manner, determines the relative strength between BLIMP-1 and BACH2 in individual MBCs, and thereby dictates their individual probabilities to develop into GCs or PCs upon re-stimulation.

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Limited access to antigen drives the generation of early B cell memory while restraining the plasmablast response

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