Lung B cells in ectopic germinal centres undergo affinity maturation
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ABSTRACT:
PROVIDER: PRJNA1210598 | ENA |
REPOSITORIES: ENA
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Project description:Compared with naïve B cells, the B cell receptor (BCR) signal in germinal center (GC) B cells is attenuated; however, the significance of this signaling attenuation has not been well defined. Here, to investigate the role of attenuation of BCR signaling, we employed a Csk mutant mouse model in which Csk-deficiency in GC B cells resulted in augmentation of net BCR signaling with no apparent effect on antigen presentation. We found that Csk is required for GC maintenance and efficient antibody affinity maturation. Mechanistically, ROS-induced apoptosis was exacerbated concomitantly with mitochondrial dysfunction in Csk-deficient GC B cells. Hence, our data suggest that attenuation of the BCR signal restrains hyper-ROS production, thereby protecting GC B cells from apoptosis and contributing to efficient affinity maturation.
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Project description:Humoral immune responses require germinal centres (GC) for antibody affinity maturation. Within GC, B-cell proliferation and mutation are segregated from affinity-based positive selection in the dark zone (DZ) and light zone (LZ) substructures, respectively. While IL21 is known to be important in affinity maturation and GC maintenance, here we show it is required for both establishing normal zone representation and preventing the accumulation of cells in G1 cell cycle stage in the GC LZ.
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Project description:Germinal centres (GC) are essential for the establishment of long-lasting antibody responses. In there, GC B cells rely on post-transcriptional RNA mechanisms for translating activation-associated transcriptional programs into functional changes in the cell proteome. However, we still lack knowledge about which are the critical proteins driving these key mechanisms. Here we show that the RNA binding proteins TIA1 and TIAL1 are required for the generation of long-lasting GC responses. TIA1 and TIAL1- deficient GC B cells fail to undergo antigen- mediated positive selection, expansion and differentiation into B cell clones producing high-affinity antibodies. Mechanistically, TIA1 and TIAL1 control the transcriptional identity of dark and light zone GC B cells and enable timely expression of the pro-survival molecule MCL1. Altogether, we demonstrate here that TIA1 and TIAL1 are key players in the post-transcriptional program that selects high-affinity antigen-specific GC B cells.
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Project description:Germinal centres (GC) are essential for the establishment of long-lasting antibody responses. In there, GC B cells rely on post-transcriptional RNA mechanisms for translating activation-associated transcriptional programs into functional changes in the cell proteome. However, we still lack knowledge about which are the critical proteins driving these key mechanisms. Here we show that the RNA binding proteins TIA1 and TIAL1 are required for the generation of long-lasting GC responses. TIA1 and TIAL1- deficient GC B cells fail to undergo antigen-mediated positive selection, expansion and differentiation into B cell clones producing high-affinity antibodies. Mechanistically, TIA1 and TIAL1 control the transcriptional identity of dark and light zone GC B cells and enable timely expression of the pro-survival molecule MCL1. Altogether, we demonstrate here that TIA1 and TIAL1 are key players in the post-transcriptional program that selects high-affinity antigen-specific GC B cells.
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Project description:Antibody responses are characterized by increasing affinity and diversity over time. Affinity maturation occurs in germinal centers by a mechanism that involves repeated cycles of somatic mutation and selection. How antibody responses diversify while also undergoing affinity maturation is not as well understood. Here, we examined germinal center (GC) dynamics by tracking B cell entry, division, somatic mutation and specificity. Our experiments show that naïve B cells continuously enter GCs where they compete for T cell help and undergo clonal expansion. Consistent with late entry, invaders carry fewer mutations but can contribute up to 30 % or more of the cells in late-stage germinal centers. Notably, cells entering the germinal center at later stages of the reaction diversify the immune response by expressing receptors that show low affinity to the immunogen. Paradoxically, the affinity threshold for late GC entry is lowered in the presence of high affinity antibodies.
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Project description:Antibody affinity maturation occurs in germinal centres (GC) where B cells cycle between the light zone (LZ) and the dark zone. In the LZ GC B cells bearing immunoglobulins with the highest affinity for antigen receive positive selection signals from T helper cells that promotes their rapid proliferation. Here we show that the RNA binding protein PTBP1 is necessary for the progression of GC B cells through late S-phase of the cell cycle and for affinity maturation. PTBP1 is required for the expression of the c-MYC-dependent gene programme induced in GC B cells receiving T cell help and directly regulates the alternative splicing of transcripts increased during positive selection to promote anabolic metabolism and cell proliferation.
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