Journal articles on the topic 'GC B cell'
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1
Lopez-Ocasio, Maria D. "T Follicular Regulatory (TFR) Cells Regulate B Cell Responses in Both, T-cell Dependent and Independent Pathways." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 48.9. http://dx.doi.org/10.4049/jimmunol.200.supp.48.9.
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Abstract Production of high-affinity antibody-secreting plasma cells and memory B cells requires interaction of TFH cells with B cells in the follicle. TFR cells, a subset of Foxp3+ Tregs, localize into follicles, regulating GC responses. To elucidate the mechanisms and cellular targets used by TFR cells to suppress GC responses, we quantitated their function in vitro. In the absence of TFR cells, TFH from primed mice induce naive B cell differentiation into GC B cells and class switching in the presence of anti-CD3 alone or anti-IgM/anti-CD3 in a contact dependent manner. Addition of TFR cells from primed mice efficiently suppressed GC B cell differentiation and class switching in the anti-CD3 alone cultures, but moderately suppressed BCR-stimulated B cells. Under anti-CD3 conditions, IL-4−/− TFH cells did not promote B cell differentiation and class switching. In contrast, IL-21R−/− B cells differentiated into GC B cells with a reduced number of IgG1+ cells. When IL-4−/− TFH cells were co-cultured with IL-21R−/− B cells, both GC differentiation and class switching were reduced. Under anti-IgM/anti-CD3 conditions, IL-4−/− TFH cells promoted B cell differentiation, but class switching was reduced, while IL-21R−/− B cells differentiated normally into GC B cells, with reduced class switching. When B cells alone were stimulated in culture with either LPS or CpG, TFR cells did not block B cell proliferation, but their differentiation into plasma cells was reduced. These studies suggest that in vitro, TFR cells regulate GC responses primarily by acting on TFH cells by inhibiting cytokine production and CD40L expression, but can also directly suppress some aspects of B cell differentiation. Supported by the Intramural Research Program of the NIAID.
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Jones, Derek, Irene Chernova, and David Allman. "B cell-intrinsic mTOR signaling regulates the generation of germinal center B cells (IRM8P.716)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 127.17. http://dx.doi.org/10.4049/jimmunol.192.supp.127.17.
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Abstract Germinal centers (GCs) are sites enriched for proliferative B cells undergoing class switch, somatic hypermutation, and selection for clones expressing high-affinity antigen-specific receptors. GCs are a main source of long-lived plasma cells (PCs) and memory B cells, and many B-lineage cancers including multiple myeloma (MM), a malignancy of PCs, also originate in GCs. However, little is known about the biochemical pathways regulating GC B cells or GC-derived effectors. Thus, we sought to define the role of mammalian target of rapamycin (mTOR), a serine/threonine kinase known to regulate several biochemical pathways needed for cell growth, division, and survival, in the maintenance of GC B cells and GC-derived cells. To address the role of mTOR in GC B cell generation, we treated NP-CGG-immunized mice with rapamycin, an mTOR inhibitor. Rapamycin treatment caused a near-complete loss of NP-specific GC B cells in the spleen, and a selective reduction of newly formed bone marrow PCs. We next generated Raptorf/f x CD20-ER-Cre mice to induce B cell-specific deletion of the mTOR-requisite protein Raptor; Raptor deletion caused the ablation of antigen-specific GCs, as well as secondary antibody responses mediated by memory B cells. The data indicate that GC B cells utilize mTOR signaling to regulate metabolic pathways required for cell division and/or survival. Future studies will address the notion that malignant PCs responsible for MM must be replenished by ongoing GC responses.
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Sewastianik, Tomasz, Juerg R. Straubhaar, Jian-Jun Zhao, Mehmet K. Samur, Keith Adler, Helen E. Tanton, Vignesh Shanmugam, et al. "miR-15a/16-1 deletion in activated B cells promotes plasma cell and mature B-cell neoplasms." Blood 137, no. 14 (April 8, 2021): 1905–19. http://dx.doi.org/10.1182/blood.2020009088.
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Abstract Chromosome 13q deletion [del(13q)], harboring the miR-15a/16-1 cluster, is one of the most common genetic alterations in mature B-cell malignancies, which originate from germinal center (GC) and post-GC B cells. Moreover, miR-15a/16 expression is frequently reduced in lymphoma and multiple myeloma (MM) cells without del(13q), suggesting important tumor-suppressor activity. However, the role of miR-15a/16-1 in B-cell activation and initiation of mature B-cell neoplasms remains to be determined. We show that conditional deletion of the miR-15a/16-1 cluster in murine GC B cells induces moderate but widespread molecular and functional changes including an increased number of GC B cells, percentage of dark zone B cells, and maturation into plasma cells. With time, this leads to development of mature B-cell neoplasms resembling human extramedullary plasmacytoma (EP) as well as follicular and diffuse large B-cell lymphomas. The indolent nature and lack of bone marrow involvement of EP in our murine model resembles human primary EP rather than MM that has progressed to extramedullary disease. We corroborate human primary EP having low levels of miR-15a/16 expression, with del(13q) being the most common genetic loss. Additionally, we show that, although the mutational profile of human EP is similar to MM, there are some exceptions such as the low frequency of hyperdiploidy in EP, which could account for different disease presentation. Taken together, our studies highlight the significant role of the miR-15a/16-1 cluster in the regulation of the GC reaction and its fundamental context-dependent tumor-suppression function in plasma cell and B-cell malignancies.
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Lopez-Ocasio, Maria D., and Ethan M. Shevach. "T Follicular Regulatory (TFR) Cells Regulate B Cell Responses By Targeting TF Helper (TFH) Cells." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 223.11. http://dx.doi.org/10.4049/jimmunol.198.supp.223.11.
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Abstract Interaction of TFH cells with B cells not only helps TFH to fully commit to this lineage, but also provides B cells with survival and differentiation cues. A GC response is critical for the development of an immune response against pathogens, but a dysregulated response could lead to autoantibody production. TFR cells, a subset of Foxp3+ Tregs, localize into follicles to regulate GC responses. To elucidate the mechanism (s) and cellular target (s) utilized by TFR cells to suppress GC responses, we quantitated TFR function in vitro. In the absence of TFR cells, TFH from primed mice induce both naive B cell differentiation into GC B cells and class switching in the presence of anti-CD3 alone or anti-IgM/anti-CD3 in a contact dependent manner. Addition of TFR cells from primed mice efficiently suppressed GC B cell proliferation, differentiation and class switching in the anti-CD3 alone cultures, but only moderately suppressed BCR-stimulated B cells. Under anti-CD3 conditions, IL-4-deficient TFH cells did not promote B cell differentiation and class switching. In contrast, IL-21R-deficient B cells differentiated into GC B cells with a reduced number of IgG1+ cells. When IL-4 deficient TFH cells were co-cultured with IL-21R-deficient B cells, both GC differentiation and class switching were reduced. Under anti-IgM/anti-CD3 conditions, IL-4-deficient TFH cells promoted B cell differentiation, but class switching was reduced, while IL-21R-deficient B cells differentiated normally into GC B cells, but class switching was reduced. These studies suggest that at least in vitro, TFR cells regulate the GC responses by acting directly on TFH cells most likely by inhibiting cytokine production.
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Ding, Chuanlin, and Jun Yan. "Pivotal role of STAT3 signaling in germinal center B cell and T follicular helper cell differentiation (IRC3P.458)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 59.1. http://dx.doi.org/10.4049/jimmunol.192.supp.59.1.
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Abstract Germinal center (GC) B cells and T follicular helper (Tfh) cells are critical for long-lived plasma cell differentiation and high-affinity antibody production in response to T cell-dependent antigens. Previous studies demonstrated that GC formation was intact in the absence of STAT3 in B cells at day 12. However, emerging evidence suggests that IL-21/STAT3 signaling is a potent regulator for B cell differentiation. To better understand the role of STAT3 in the kinetics of GC formation and GC B cell response, we assessed GC B cells at consecutive time points following immunization with antigen OVA. In B cell conditional STAT3-dificient mice, fewer GC and GC B cells were generated upon immunization in the late phase (day 21) but not on day 14 compared with that of control mice. Increased cell death and decreased cell proliferation were found in the STAT3 deficient GC B cells. Consequently, plasma cell differentiation and antibody production were impaired in B cell STAT3-deficient mice. In addition, the Tfh cell response was correlated with the magnitude of the GC B cell response and significantly decreased in B cell STAT3-deficient mice. Furthermore, GC B cells and autoantibody production were also significantly decreased in autoreactive B cell STAT3-deficient mice after apoptotic cell immunization. These data provide new insights into the GC and Tfh differentiation and the function of STAT3 in humoral immune responses.
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Benet, Zachary, Rita Wu, Matangi Marthi, Jackson Turner, and Irina Grigorova. "B cell-intrinsic production of CCL3/4 promotes direct sampling of Germinal Center B cells by T follicular regulatory cells and limits non-foreign antigen specific B cell response." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 195.13. http://dx.doi.org/10.4049/jimmunol.196.supp.195.13.
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Abstract A hallmark of adaptive humoral immunity is the germinal center (GC) reaction. GCs are the primary site of antigen-dependent clonal expansion, immunoglobulin diversification, and affinity maturation and give rise to memory cells and long-lived plasma cells that secrete high-affinity antibodies. These coordinated processes in GCs are highly dependent on cognate follicular T cells. Previous studies and our findings suggest increased expression of proinflammatory chemokines CCL3/4 in GC centrocytes. However, the role of CCL3/4 for centrocyte interactions with follicular T cells and regulation of humoral immunity is poorly understood. We found that B cell intrinsic production of CCL3/4 is required for control of B cell expansion within GCs and restrict the development of class-switched anti-nuclear antibodies following immunization with foreign antigen. We determined that follicular regulatory T cells (Tfr) respond to CCL3/4 chemokines ex vivo and interact more frequently with WT compared to CCL3-deficient GC B cells in vivo using two photon microscopy. Finally, we have identified a subpopulation of GC centrocytes that have significantly increased expression levels of CCL3/4. These data suggests that CCL3/4 secreted by a subset of GC B cells promotes their direct interactions with Tfr cells and plays a role in the elimination of potentially self-reactive B cell clones within GCs.
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Rea, I. Maeve. "Activated P13Kδ disrupts germinal center GC T(fh)/GC B cell cross talk and B cell antibody coding." Cellular & Molecular Immunology 16, no. 11 (October 8, 2019): 848–50. http://dx.doi.org/10.1038/s41423-019-0295-0.
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Grigorova, Irina, and Jackson S. Turner. "Dissecting the contribution of antigen-dependent B cell receptor engagement and T cell help to Germinal Center B cell selection and differentiation." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 107.9. http://dx.doi.org/10.4049/jimmunol.200.supp.107.9.
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Abstract Proper selection of somatically hyper mutated B cells in the Germinal Centers (GCs) and their differentiation into long-lived plasma cells is key for the development of high-affinity long-term humoral immunity. However, relative contribution towards GC B cell selection by the two key factors: antigen-driven B cell receptor (BCR) signaling and T cell help, remains an open question. We have addressed this long-standing question in the field using an experimental model that enables independent manipulation of both antigen-driven BCR engagement and antigenic peptide presentation in GC B cells. Our studies suggest that in the absence of antigen-driven BCR engagement, T cell help is sufficient for robust selection of GC B cells and their differentiation into plasmablasts. In contrast, neither is induced by antigen-dependent BCR crosslinking in the absence of T cell help. Interestingly, when the levels of MHCII/peptide presentation by GC B cells are suboptimal, antigen-dependent BCR engagement can synergize with T cell help to promote selection of GC B cells and their differentiation into plasmablasts. Our findings reconcile somewhat contradictory data reported in previous studies and point towards the importance of the two signal model in the GC response.
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Saniee, Avva, Kihyuck Kwak, Nicolas Quizon, Haewon Sohn, Javier Manzella-Lapeira, Prasida Holla, Jinghua Lu, et al. "Human germinal center B cells are intrinsically able to discriminate antigen affinity and with T cell help express plasma cell transcription factors." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 107.17. http://dx.doi.org/10.4049/jimmunol.200.supp.107.17.
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Abstract The selection of GC B cells that express high affinity B cell receptors (BCRs) is driven by the ability of B cells to both signal through the BCR and to extract antigen and present it to follicular helper T cells (T FH cells). Using anti-kappa antibodies of low (KD=3.9×10 −7 ) versus high (KD=2.4×10 −9 ) affinities attached to membranes as surrogate antigens, we show that LZ GC B cells are able to discriminate between these and responded only to the high affinity antigen. In contrast, naïve B cells responded to both high and low affinity antigens. LZ GC B cells engaged membrane associated surrogate antigens through highly dynamic F-actin and ezrin-rich pod-like structures that concentrated BCRs at their contact points. Using DNA-based mechanical force nano-sensors we observed robust pulling forces localized to the contact sites of the pods with the membrane. In contrast, naïve B cells formed flat stable contacts with the membranes and showed only defuse weak pulling forces. GC B cells optimally express transcription factors that drive plasma cell differentiation, namely IRF-4 and PRDM-1, in response to antigen in combination with T FH help while naïve B cells increased IRF-4 and PRDM-1 transcription in response to T FH alone and less so to antigen alone. Thus, LZ GC B cells appear to be intrinsically capable of antigen affinity discrimination and with the acquisition of T FH help BCR-activated LZ GC B cells differentiate into plasma cells.
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De La Pena Enterina, Jhon Ralph, Susmita Sarkar, and Matthew Macauley. "Glycan Remodelling Controls Germinal Centre B cell Responses." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 71.3. http://dx.doi.org/10.4049/jimmunol.204.supp.71.3.
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Abstract Germinal centre (GC) B cells are routinely identified through distinct changes on their surface carbohydrates, called glycans; yet, whether these modifications play an essential role in GC reaction remain unknown. One striking change relates to the monosaccharide sialic acid. In mice, this change is mediated through downregulation of an enzyme called Cmah. As a consequence, GC B cells lose the preferred ligand for CD22, a member of the sialic acid-binding immunoglobulin-type lectins (Siglecs) and a co-inhibitory receptor of the B cell antigen receptor. Since CD22 regulates B cell function, we hypothesize that this specific glycan remodelling on B cells control the GC reaction by modulating the activity of CD22. To test our hypothesis, we developed a mouse model that constitutively expresses Cmah in B cells. Following immunization, we find that sustained expression of Cmah in B cells results in impaired generation of antigen-specific GC B cells. More significantly, this observed defect is dependent on CD22, highlighting that coordinated loss of preferred ligands for CD22 on B cells plays a critical function in the GC. Furthermore, antibody affinity maturation is significantly impaired in immunized mice harbouring B cells which lack either CD22 or its cis glycan ligands, further supporting the role of CD22 and its glycan ligands in the GC. Ongoing efforts are focused on defining the GC-specific nature of these observations and examining potential mechanism related to BCR signalling, GC B cell survival and exit to plasma cells, and B-T cell interactions.
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Pasqualucci, Laura, and Ulf Klein. "NF-κB Mutations in Germinal Center B-Cell Lymphomas: Relation to NF-κB Function in Normal B Cells." Biomedicines 10, no. 10 (October 1, 2022): 2450. http://dx.doi.org/10.3390/biomedicines10102450.
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Most B cell lymphomas arise from the oncogenic transformation of B cells that have undergone the germinal center (GC) reaction of the T cell-dependent immune response, where high-affinity memory B cells and plasma cells are generated. The high proliferation of GC B cells coupled with occasional errors in the DNA-modifying processes of somatic hypermutation and class switch recombination put the cell at a risk to obtain transforming genetic aberrations, which may activate proto-oncogenes or inactivate tumour suppressor genes. Several subtypes of GC lymphomas harbor genetic mutations leading to constitutive, aberrant activation of the nuclear factor-κB (NF-κB) signaling pathway. In normal B cells, NF-κB has crucial biological roles in development and physiology. GC lymphomas highjack these activities to promote tumour-cell growth and survival. It has become increasingly clear that the separate canonical and non-canonical routes of the NF-κB pathway and the five downstream NF-κB transcription factors have distinct functions in the successive stages of GC B-cell development. These findings may have direct implications for understanding how aberrant NF-κB activation promotes the genesis of various GC lymphomas corresponding to the developmentally distinct GC B-cell subsets. The knowledge arising from these studies may be explored for the development of precision medicine approaches aimed at more effective treatments of the corresponding tumours with specific NF-κB inhibitors, thus reducing systemic toxicity. We here provide an overview on the patterns of genetic NF-κB mutations encountered in the various GC lymphomas and discuss the consequences of aberrant NF-κB activation in those malignancies as related to the biology of NF-κB in their putative normal cellular counterparts.
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Quizon, Nicolas, Kihyuck Kwak, Haewon Sohn, and Susan K. Pierce. "Human germinal center B cells are intrinsically distinct from naive B cells." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 52.4. http://dx.doi.org/10.4049/jimmunol.198.supp.52.4.
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Abstract In germinal centers (GCs) B cells undergo cycles of proliferation and somatic hyper mutation followed by affinity discrimination. Selection of GC B cells expressing high affinity B cell receptors (BCRs) is driven by the ability of B cells to signal through the BCR and extract antigen to present to follicular helper T cells. Here we provide evidence that human tonsillar GC B cells, as compared to naïve tonsillar B cells, may have a higher threshold for affinity selection but be better able to interact with T cells and, once triggered through the BCR, may form more stable signaling complexes. A comprehensive quantitative analysis of surface proteins showed distinct profiles for naïve and GC B cells. In particular, GC B cells express less of the integrin VLA-4 and as a consequence were less able to engage beads coated with its ligand, VCAM-1. Given that VLA-4 tethers B cells to VCAM-expressing cell surfaces and facilitates BCR-dependent activation, a reduction in VLA-4 expression would be predicted to raise the threshold for affinity selection in GC B cells. GC B cells also tended to have increased surface expression of proteins that mediate T-B-cell interactions, such as CD80 and CD86, suggesting that once antigen is captured and presented GC B cells would be better equipped to engage helper T cells. To explore BCR signaling we imaged synapses formed between B cells with anti-Ig-containing planar lipid bilayers via total internal reflection fluorescence microscopy. GC B cells tended to form more stable signaling complexes showing greater co-localization between their BCRs and components of their signaling pathway. Taken together these data point toward intrinsic differences between GC and naïve B cells that may contribute to the outcome of GC responses.
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Nayak, Bishnu P., Anshu Agarwal, Pooja Nakra, and Kanury V. S. Rao. "B Cell Responses to a Peptide Epitope. VIII. Immune Complex-Mediated Regulation of Memory B Cell Generation Within Germinal Centers." Journal of Immunology 163, no. 3 (August 1, 1999): 1371–81. http://dx.doi.org/10.4049/jimmunol.163.3.1371.
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Abstract Using an in vivo reconstitution assay, we examine here the role of immune complexes in both formation of germinal centers (GC) and processes that occur subsequently within. The presence of Ag, as immune complexes, was found not to constitute a limiting requirement for the initiation of GC formation. No detrimental effect either on numbers or sizes of the resulting GC was observed when Ag-containing immune complexes were omitted during reconstitution. Thus, both recruitment and proliferation of Ag-activated B cells within GC appear not to be limited by Ag concentrations. In contrast, the presence of immune complexes was observed to be obligatory for the generation of Ag-specific memory B cells. This optimally required immune complexes to be constituted by IgG-class Abs with epitope specificities that were homologous to those of the GC B cells. The GC reaction was also found to be characterized by an enhancement of Ab specificity for the homologous epitope. Although some improvement in specificity was noted in recall responses from immune complex-deficient GC, the presence of appropriate immune complexes served to further optimize the outcome. Here again, isotype and epitope-specificity of the Ab constituent in immune complexes proved to be important.
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Choe, J., H. S. Kim, R. J. Armitage, and Y. S. Choi. "The functional role of B cell antigen receptor stimulation and IL-4 in the generation of human memory B cells from germinal center B cells." Journal of Immunology 159, no. 8 (October 15, 1997): 3757–66. http://dx.doi.org/10.4049/jimmunol.159.8.3757.
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Abstract The germinal center (GC) is an anatomical site where memory B cells are generated. Ag-Ab complexes presented by follicular dendritic cells in GC select precursors of memory B cells. Using a unique in vitro experimental system in which the survival of GC B cells is supported by a defined follicular dendritic cell-like cell line, we investigated the effects of B cell Ag receptor (BCR) stimulation and IL-4 on the memory B cell generation from centroblasts. IL-4 is reported to be critical for GC formation. Centroblasts differentiated to centrocytes during the culture period of 3 days as demonstrated by the down-regulation of CD77 expression and induction of CD44 as well as Bcl-2 expression. The transition of centroblast to centrocyte was enhanced by BCR stimulation and IL-4. Upon further culture, the centrocytes differentiated to memory B cells, a process that was enhanced by BCR stimulation and IL-4. The presence of IL-4 in the culture did not increase the number of plasma cells. These experimental data provide formal in vitro evidence that Ags in GC may participate not only in the selection but also in the expansion of memory B cells and that IL-4 is a growth factor promoting this expansion.
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Jing, Zhixin, Mark McCarron, and David R. Fooksman. "Role of peptide-MHCII complexes in germinal center B cell selection and plasma cell differentiation." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 71.4. http://dx.doi.org/10.4049/jimmunol.204.supp.71.4.
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Abstract Germinal center (GC) selection is critical for generating affinity-matured antibodies in T-cell-dependent immune responses. Despite the essential help follicular T cells provide to GC B cells, it is unclear how GC B cell fate decisions are made. Although cognate peptide-MHCII (pMHCII) is critical for T cell help, how pMHCII density directly contributes to B cell selection and cell fate remain unclear. The a-DEC205-OVA (dec) model system has been widely used to interrogate GC B selection, by enhancing selection of WT (Ly75+/+) B cells over untargeted Ly75−/− (KO) B cells. However, under these conditions, it is unclear what the fate of B cells presenting intermediate levels of pMHCII is and whether T cell help is indeed limited. To investigate these questions, we used Ly75+/− (DEC-het) B cells, which expressed intermediate levels (~50%) of surface DEC205 protein compared to WT B cells, and presented proportional amount of OVA peptide after dec treatment. Using competitive transfers, we found that WT B cells expanded two-fold more than DEC-het B cells. This 2-fold difference in expansion was maintained at a wide range of dec administration, indicating that in vivo, T cells can distinguish different densities of pMHCII on multiple B cells in the same GC and respond proportionally. Surprisingly, we found that upon dec stimulation, both WT and DEC-het GC B cells were equally capable of differentiating into plasma cells, suggesting that pMHCII density does not control B cell fate directly. Blocking of CD40 signaling removed the two-fold advantage of WT over DEC-het B cells during selection after dec treatment, suggesting CD40 signaling is proportional to pMHCII density. These results provide new interpretations of how GC selection occurs in vivo.
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Chodisetti, Sathi Babu, Adam Fike, Kristen Bricker, Phillip P. Domeier, Nicholas M. Choi, and Ziaur Rahman. "B cell-intrinsic STAT3 regulates the germinal center dark zone." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 151.20. http://dx.doi.org/10.4049/jimmunol.204.supp.151.20.
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Abstract Germinal centers (GCs) are sites for antibody diversification, somatic hypermutation (SHM) and antigen specific B cell selection. GCs are anatomically divided into two distinct areas known as dark zone (DZ) and light zone (LZ) where SHM and clonal selection occurs, respectively. Although previous studies have suggested a B cell-intrinsic role of STAT3 in GC maintenance and antibody responses, how STAT3 signaling in B cells may maintain GCs for B cell selection is not clear. Using immunization and infection models, we show that STAT3 in B cells regulates the GC DZ, resulting in decreased high affinity antibody production. STAT3 deficient DZ B cells demonstrate a decreased cell proliferation and increased apoptotic activity. Further, STAT3 deletion in B cells led to defects in plasma cell formation and B cell memory response. Using GC B cell specific STAT3 conditional knockout mice and GC B cell culture system, we show that STAT3 deficient GC B cells display low amounts of FOXO1, a critical transcription factor required for GC DZ program. Transcriptomic analysis of GC B cells from STAT3 deficient and sufficient mice reveals STAT3-mediated gene regulation of multiple cellular pathways known to be involved in GC DZ maintenance. In conclusion, STAT3 signaling in B cells controls the GC DZ, which, in turn, helps maintain GCs for high-affinity antibody production. Our findings identify STAT3 as a novel target for enhancing humoral immunity as well as for the treatment of diseases involving abnormal GC activity.
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Lee, Sau K., Robert J. Rigby, Dimitra Zotos, Louis M. Tsai, Shimpei Kawamoto, Jennifer L. Marshall, Roybel R. Ramiscal, et al. "B cell priming for extrafollicular antibody responses requires Bcl-6 expression by T cells." Journal of Experimental Medicine 208, no. 7 (June 27, 2011): 1377–88. http://dx.doi.org/10.1084/jem.20102065.
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T follicular helper cells (Tfh cells) localize to follicles where they provide growth and selection signals to mutated germinal center (GC) B cells, thus promoting their differentiation into high affinity long-lived plasma cells and memory B cells. T-dependent B cell differentiation also occurs extrafollicularly, giving rise to unmutated plasma cells that are important for early protection against microbial infections. Bcl-6 expression in T cells has been shown to be essential for the formation of Tfh cells and GC B cells, but little is known about its requirement in physiological extrafollicular antibody responses. We use several mouse models in which extrafollicular plasma cells can be unequivocally distinguished from those of GC origin, combined with antigen-specific T and B cells, to show that the absence of T cell–expressed Bcl-6 significantly reduces T-dependent extrafollicular antibody responses. Bcl-6+ T cells appear at the T–B border soon after T cell priming and before GC formation, and these cells express low amounts of PD-1. Their appearance precedes that of Bcl-6+ PD-1hi T cells, which are found within the GC. IL-21 acts early to promote both follicular and extrafollicular antibody responses. In conclusion, Bcl-6+ T cells are necessary at B cell priming to form extrafollicular antibody responses, and these pre-GC Tfh cells can be distinguished phenotypically from GC Tfh cells.
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Inoue, Takeshi, Ryo Shinnakasu, Wataru Ise, Chie Kawai, Takeshi Egawa, and Tomohiro Kurosaki. "The transcription factor Foxo1 controls germinal center B cell proliferation in response to T cell help." Journal of Experimental Medicine 214, no. 4 (March 28, 2017): 1181–98. http://dx.doi.org/10.1084/jem.20161263.
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Germinal center (GC) B cells cycle between two states, the light zone (LZ) and the dark zone (DZ), and in the latter they proliferate and hypermutate their immunoglobulin genes. How this functional transition takes place is still controversial. In this study, we demonstrate that ablation of Foxo1 after GC development led to the loss of the DZ GC B cells and disruption of the GC architecture, which is consistent with recent studies. Mechanistically, even upon provision of adequate T cell help, Foxo1-deficient GC B cells showed less proliferative expansion than controls. Moreover, we found that the transcription factor BATF was transiently induced in LZ GC B cells in a Foxo1-dependent manner and that deletion of BATF similarly led to GC disruption. Thus, our results are consistent with a model where the switch from the LZ to the DZ is triggered after receipt of T cell help, and suggest that Foxo1-mediated BATF up-regulation is at least partly involved in this switch.
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Natkunam, Yasodha, Shuchun Zhao, David Y. Mason, Jun Chen, Behnaz Taidi, Margaret Jones, Anne S. Hammer, Stephen Hamilton Dutoit, Izidore S. Lossos, and Ronald Levy. "The oncoprotein LMO2 is expressed in normal germinal-center B cells and in human B-cell lymphomas." Blood 109, no. 4 (October 12, 2006): 1636–42. http://dx.doi.org/10.1182/blood-2006-08-039024.
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Abstract We previously developed a multivariate model based on the RNA expression of 6 genes (LMO2, BCL6, FN1, CCND2, SCYA3, and BCL2) that predicts survival in diffuse large B-cell lymphoma (DLBCL) patients. Since LMO2 emerged as the strongest predictor of superior outcome, we generated a monoclonal anti-LMO2 antibody in order to study its tissue expression pattern. Immunohistologic analysis of over 1200 normal and neoplastic tissue and cell lines showed that LMO2 protein is expressed as a nuclear marker in normal germinal-center (GC) B cells and GC-derived B-cell lines and in a subset of GC-derived B-cell lymphomas. LMO2 was also expressed in erythroid and myeloid precursors and in megakaryocytes and also in lymphoblastic and acute myeloid leukemias. It was rarely expressed in mature T, natural killer (NK), and plasma cell neoplasms and was absent from nonhematolymphoid tissues except for endothelial cells. Hierarchical cluster analysis of immunohistologic data in DLBCL demonstrated that the expression profile of the LMO2 protein was similar to that of other GC-associated proteins (HGAL, BCL6, and CD10) but different from that of non-GC proteins (MUM1/IRF4 and BCL2). Our results warrant inclusion of LMO2 in multivariate analyses to construct a clinically applicable immunohistologic algorithm for predicting survival in patients with DLBCL.
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Seifert, Marc, and Ralf Küppers. "Molecular footprints of a germinal center derivation of human IgM+(IgD+)CD27+ B cells and the dynamics of memory B cell generation." Journal of Experimental Medicine 206, no. 12 (November 16, 2009): 2659–69. http://dx.doi.org/10.1084/jem.20091087.
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The origin of IgM+CD27+ B lymphocytes with mutated IgV genes, which account for ∼20% of human peripheral blood (PB) B cells, is controversially discussed. A generation in a primary diversification pathway, in T cell–independent immune responses, or in T cell–dependent germinal center (GC) reactions has been proposed. We show here that IgM+IgD+CD27+ and IgM+IgD−/lowCD27+ B cell subsets carry, like class-switched memory B cells, mutations in the Bcl6 gene as a genetic trait of a GC experience. Moreover, the identification of PB IgM+IgD+CD27+ B cells clonally related to GC-derived IgG+ memory B cells with shared and distinct IgV gene mutations demonstrates the GC origin also of the former subset. These findings provide genetic evidence for a GC derivation of somatically mutated IgM+ B cells and indicate that adult humans harbor a large population of IgM+IgD+ post-GC memory B cells. Furthermore, the analysis revealed that a highly diverse and often very large population of memory B cells is generated from a given GC B cell clone, and that (preferentially IgM) memory B cells are generated already early in the GC reaction. This provides novel insights into the dynamics of GC reactions and the generation of a memory B cell repertoire.
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Chen, Shuwen, Masaki Miyazaki, Vivek Chandra, Kathleen M. Fisch, Aaron N. Chang, and Cornelis Murre. "Id3 Orchestrates Germinal Center B Cell Development." Molecular and Cellular Biology 36, no. 20 (July 25, 2016): 2543–52. http://dx.doi.org/10.1128/mcb.00150-16.
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Previous studies have demonstrated that E proteins induce activation-induced deaminase (AID) expression in activated B cells. Here, we examined the role of Id3 in germinal center (GC) cells. We found that Id3 expression is high in follicular B lineage cells but declines in GC cells. Immunized mice with Id3 expression depleted displayed a block in germinal center B cell maturation, showed reduced numbers of marginal zone B cells and class-switched cells, and were associated with decreased antibody titers and lower numbers of plasma cells.In vitro, Id3-depleted B cells displayed a defect in class switch recombination. Whereas AID levels were not altered in Id3-depleted activated B cells, the expression of a subset of genes encoding signaling components of antigen receptor-, cytokine receptor-, and chemokine receptor-mediated signaling was significantly impaired. We propose that during the GC reaction, Id3 levels decline to activate the expression of genes encoding signaling components that mediate B cell receptor- and or cytokine receptor-mediated signaling to promote the differentiation of GC B cells.
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Zhang, Ting-ting, David Gonzalez, and Ann M. Haberman. "Step-wise formation of germinal center B cells is completed by a requisite phase of Th cell disengagement and CD40 signaling abstinence." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 195.3. http://dx.doi.org/10.4049/jimmunol.196.supp.195.3.
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Abstract There are conflicting reports on the role of CD40 signaling in the initiation and maintenance of germinal centers (GC). CD40 signaling invokes the nuclear translocation of RelB, a transcription factor that promotes IRF4 expression. We examined the early stages of GC B cell differentiation without any phenotypic preconceptions by the adoptive transfer of tagged antigen-specific B cells. As expected, B cells were first observed to express intermediate levels of BCL6 within the interfollicular (IF) zone shortly after immunization. However, these GC B cell precursors had only a partial GC phenotype and co-expressed RelB and IRF4, transcription factors known to repress BCL6 transcription. This initial co-expression of mutually antagonistic transcription factors is short-lived: follicular BCL6hi GC B cells with diminished levels of RelB and IRF4 emerge shortly thereafter, coupled with the disappearance of the immediate precursors as a function of cell division. Interestingly, potentiating T cell help at the GC initiation stage blocks this transition and diverts the fate of GC immediate precursors towards plasma cells, suggesting that ongoing T cell engagement discourages GC B cell formation. Consistent with this idea, we found that reducing the amount of antigen at the time of immunization accelerates GC B cell formation. Similarly, discontinuing T-cell derived factors in an in-vitro culture system promotes the generation of BCL6hi RelB− IRF4− cells with GC B cell properties. Taken together these results suggest that CD40 signaling in B cells is necessary to generate the immediate precursors of GC B cells, but transition to the BCL6hi follicular state is completed by a period of abstinence from Th cell CD40L.
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Tsubata, Takeshi. "B-cell tolerance and autoimmunity." F1000Research 6 (March 29, 2017): 391. http://dx.doi.org/10.12688/f1000research.10583.1.
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Self-reactive B cells are tolerized at various stages of B-cell development and differentiation, including the immature B-cell stage (central tolerance) and the germinal center (GC) B-cell stage, and B-cell tolerance involves various mechanisms such as deletion, anergy, and receptor editing. Self-reactive B cells generated by random immunoglobulin variable gene rearrangements are tolerized by central tolerance and anergy in the periphery, and these processes involve apoptosis regulated by Bim, a pro-apoptotic member of the Bcl-2 family, and regulation of B-cell signaling by various phosphatases, including SHIP-1 and SHP-1. Self-reactive B cells generated by somatic mutations during GC reaction are also eliminated. Fas is not directly involved in this process but prevents persistence of GC reaction that allows generation of less stringently regulated B cells, including self-reactive B cells. Defects in self-tolerance preferentially cause lupus-like disease with production of anti-nuclear antibodies, probably due to the presence of a large potential B-cell repertoire reactive to nucleic acids and the presence of nucleic acid-induced activation mechanisms in various immune cells, including B cells and dendritic cells. A feed-forward loop composed of anti-nuclear antibodies produced by B cells and type 1 interferons secreted from nucleic acid-activated dendritic cells plays a crucial role in the development of systemic lupus erythematosus.
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Al-Khinji, Aisha, Ellen Leich, Tathiana Andrade, Alyssa Bouska, Waseem Lone, Stefan Constinean, Kai Fu, Andreas Rosenwald, Wing Chung Chan, and Javeed Iqbal. "Molecular Features of Germinal Cell Derived B-Cell Lymphomas Using miRNA Signatures." Blood 128, no. 22 (December 2, 2016): 5288. http://dx.doi.org/10.1182/blood.v128.22.5288.5288.
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Abstract Background: B-cell development is a complex biological process that initiates in bone marrow and matures in lymph nodes. These hierarchical stages are tightly regulated by transcription factors and microRNAs (miRNAs). B-cells are prone to genetic alteration during these maturation stages due to DNA breaks required for B-cell receptor re-arrangement and additional changes that occur during the germinal center (GC)-reaction for class switch recombination and somatic hypermutation. The unwarranted genomic changes resulting from these processes can lead to B-cell malignancies with varied clinical and pathological characteristics. Of the lymphoma subtypes derived from mature B-cells, a subset of diffuse large B-cell lymphoma (DLBCL), primary mediastinal large cell lymphoma (PMBL), follicular lymphoma (FL) and Burkitt lymphoma (BL) are putatively derived from GC B-cells, with varied morphological, pathological and clinical characteristics. These tumor are characterized by distinct genetic abnormalities,[ t(14;18) in GCB-DLCBL, and FL or t(8;14)] in BL, and mutational profile. We postulate miRNA expression signatures, may also explain the wide-ranging clinico-pathological characteristics of these GC B- cell derived tumors. Methods: We performed a meta-analysis of miRNA profiles of DLBCL, BL, PBML, FL and EBV+DLBCL performed by us or others. (Iqbal 2015; 2012; Leich 2011; Andrade 2014). We also included lymphomas derived from naïve B-cells (MCL, SLL) and post GC B-cells (activated B cells like ABC-DLBCL), EBV (+) DLBCL, normal B-cell subsets and cell lines of distinct B-cell lineages. The majority of the cases have been characterized by gene expression profiling (GEP) with corresponding pathological clinical characteristics in above studies. The data was obtained using Taqman® human microRNA array (Applied Biosystems, CA) containing 380 miRNAs and analyzed using BRB-array Tools. Results In our initial miRNA expression profile of 249 lymphomas including GCB-DLBCL (n=34), ABC-DLBCL(n= 29), PMBL(n= 9), BL(n= 33), FL (n= 32), EBV+DLBCL (n=8); MCL(n=30) and SLL(n=12)showed distinct hierarchical clusters enriched with GEP defined subgroup, with few interspersed cases from other subgroups suggesting that miRNAs can complement and delineate GEP defined molecular subgroups, an observation consistent with earlier findings (Iqbal 2015). When we examined miRNAs, that are specifically associated with GC B- derived lymphomas, we observed a subset of miRNA including miR-146a, miR-142-3p, miR-17, miR19b, and miR106a were present at higher levels (top 5% in abundance by CT values) in GC B lymphomas. Of these, somatic mutations in miR142 have been recently reported in GC derived lymphomas (Alyssa, Leukemia 2016). These miRNAs also represented the most abundant miRNAs in centroblast, suggesting lineage specificity of miRNA signature in these lymphomas. However, miR222 highly expressed in centroblast was not expressed at higher levels in GCB-DLBCL and BL. A number of miRNAs specifically abundant in distinct lymphomas included (BL: miR-20a, miR-16), (GCB-DLBCL: miR-223, miR-24) and (FL: miR222). MiR-150 was highly expressed in NHLs putatively derived from naive B-cells like MCL or SLL, but absent from GC-derived NHLs. Consistent with this, miR-150 was present in naive B-cells, but not in centroblast, suggesting that miR-150 may have discrete function during early B-cell differentiation and late maturation stages. Within GC derived lymphoma, we examined miRNA profiles in clinically aggressive (BL); indolent lymphomas (FL) and intermediate aggressive (GCB-DLBCL) and their association with normal B-cell subsets, and indeed a number of miRNAs (ex. miR-150) were associated with indolent lymphomas, whereas a subset of miRNAs was present in aggressive lymphomas (ex. miR-16), suggesting these miRNAs may contribute the distinct clinical characteristics. Though we have identified unique miRNA profiles in these GC derived NHLs, the target genes of these miRNAs remains to be identified. Conclusion: We identified microRNAs that were differentially expressed between GC-derived DLBCL and other lymphomas, which may help explain distinguishing features of these lymphomas. Disclosures No relevant conflicts of interest to declare.
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Minamitani, Takeharu, Teruhito Yasui, Yijie Ma, Hufeng Zhou, Daisuke Okuzaki, Chiau-Yuang Tsai, Shuhei Sakakibara, Benjamin E. Gewurz, Elliott Kieff, and Hitoshi Kikutani. "Evasion of affinity-based selection in germinal centers by Epstein–Barr virus LMP2A." Proceedings of the National Academy of Sciences 112, no. 37 (August 24, 2015): 11612–17. http://dx.doi.org/10.1073/pnas.1514484112.
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Epstein–Barr virus (EBV) infects germinal center (GC) B cells and establishes persistent infection in memory B cells. EBV-infected B cells can cause B-cell malignancies in humans with T- or natural killer-cell deficiency. We now find that EBV-encoded latent membrane protein 2A (LMP2A) mimics B-cell antigen receptor (BCR) signaling in murine GC B cells, causing altered humoral immune responses and autoimmune diseases. Investigation of the impact of LMP2A on B-cell differentiation in mice that conditionally express LMP2A in GC B cells or all B-lineage cells found LMP2A expression enhanced not only BCR signals but also plasma cell differentiation in vitro and in vivo. Conditional LMP2A expression in GC B cells resulted in preferential selection of low-affinity antibody-producing B cells despite apparently normal GC formation. GC B-cell–specific LMP2A expression led to systemic lupus erythematosus-like autoimmune phenotypes in an age-dependent manner. Epigenetic profiling of LMP2A B cells found increased H3K27ac and H3K4me1 signals at the zinc finger and bric-a-brac, tramtrack domain-containing protein 20 locus. We conclude that LMP2A reduces the stringency of GC B-cell selection and may contribute to persistent EBV infection and pathogenesis by providing GC B cells with excessive prosurvival effects.
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Middendorp, Sabine, Yanling Xiao, Ji-Ying Song, Victor Peperzak, Peter H. L. Krijger, Heinz Jacobs, and Jannie Borst. "Mice deficient for CD137 ligand are predisposed to develop germinal center–derived B-cell lymphoma." Blood 114, no. 11 (September 10, 2009): 2280–89. http://dx.doi.org/10.1182/blood-2009-03-208215.
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Abstract In the germinal center (GC), B cells proliferate dramatically and diversify their immunoglobulin genes, which increases the risk of malignant transformation. The GC B-cell reaction relies on crosstalk with follicular dendritic cells (FDCs), to which the costimulatory receptor CD137 on FDCs and its ligand on GC B cells potentially contribute. We report that mice deficient for CD137 ligand (CD137L) are predisposed to develop B-cell lymphoma, with an incidence of approximately 60% at 12 months of age. Lymphoma membrane markers were characteristic of GC B cells. Longitudinal histologic analysis identified the GC as site of oncogenic transformation and classified 85% of the malignancies found in approximately 200 mice as GC-derived B-cell lymphoma. To delineate the mechanism underlying lymphomagenesis, gene expression profiles of wild-type and CD137L-deficient GC B cells were compared. CD137L deficiency was associated with enhanced expression of a limited gene set that included Bcl-10 and the GC response regulators Bcl-6, Spi-B, Elf-1, Bach2, and activation-induced cytidine deaminase. Among these are proto-oncogenes that mediate GC B-cell lymphoma development in humans. We conclude that CD137L ordinarily regulates the GC B-cell response and thereby acts as a tumor suppressor.
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Choe, J., H. S. Kim, X. Zhang, R. J. Armitage, and Y. S. Choi. "Cellular and molecular factors that regulate the differentiation and apoptosis of germinal center B cells. Anti-Ig down-regulates Fas expression of CD40 ligand-stimulated germinal center B cells and inhibits Fas-mediated apoptosis." Journal of Immunology 157, no. 3 (August 1, 1996): 1006–16. http://dx.doi.org/10.4049/jimmunol.157.3.1006.
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Abstract To investigate the molecular and cellular mechanisms underlying the selection, differentiation, and apoptosis of germinal center (GC) B cells, we have established a culture system containing a follicular dendritic cell (FDC) line, HK. The mAb, 3C8, which is specific to HK cells and recognizes dendritic network in the GC, was developed and provided additional evidence that HK cells are related to FDC by sharing a unique surface Ag. The roles for CD40 ligand (CD40L) and T cell-derived cytokines in the differentiation of GC B cells were investigated in our culture system. We show that there are two distinct stages of GC B cell differentiation. In the early stage, GC B cells undergo spontaneous apoptosis unless they are stimulated by CD40L. In the secondary stage, IL-10 directs GC B cell differentiation toward the generation of plasma cells, while the absence of IL-10 stimulation leads to the generation of memory B cells. The major function of CD40L was found in the enhancement of cell recovery and the augmentation of memory B cell generation. Although GC B cells are Fas+, GC B cells are at first resistant to, but then become sensitive to, anti-Fas killing after 24 h in culture with CD40L, which coincides with the gradual increase in Fas expression on GC B cells. Furthermore, anti-Ig down-regulated Fas expression on CD40L-stimulated GC B cells, suggesting that Ag receptor engagement down-regulates Fas expression and prevents Fas-mediated apoptosis of GC B cells. Our data imply that GC T cells have an important role in the differentiation and apoptosis of GC B cells. GC T cells expressing both CD40L and Fas ligand have a dual function on GC B cells, helper or killer, depending on the status of target B cells. In the early stage, GC T cells stimulate the extensive proliferation of GC B cells, ensuring a large repertoire of B cells for selection. In the later stage, GC T cells kill B cells via Fas-Fas ligand interactions unless GC B cells are positively selected by Ags present on FDC.
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Chen, Chao, Sulan Zhai, Le Zhang, Jingjing Chen, Xuehui Long, Jun Qin, Jianhua Li, Ran Huo, and Xiaoming Wang. "Uhrf1 regulates germinal center B cell expansion and affinity maturation to control viral infection." Journal of Experimental Medicine 215, no. 5 (April 4, 2018): 1437–48. http://dx.doi.org/10.1084/jem.20171815.
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The production of high-affinity antibody is essential for pathogen clearance. Antibody affinity is increased through germinal center (GC) affinity maturation, which relies on BCR somatic hypermutation (SHM) followed by antigen-based selection. GC B cell proliferation is essentially involved in these processes; it provides enough templates for SHM and also serves as a critical mechanism of positive selection. In this study, we show that expression of epigenetic regulator ubiquitin-like with PHD and RING finger domains 1 (Uhrf1) was markedly up-regulated by c-Myc–AP4 in GC B cells, and it was required for GC response. Uhrf1 regulates cell proliferation–associated genes including cdkn1a, slfn1, and slfn2 by DNA methylation, and its deficiency inhibited the GC B cell cycle at G1-S phase. Subsequently, GC B cell SHM and affinity maturation were impaired, and Uhrf1 GC B knockout mice were unable to control chronic virus infection. Collectively, our data suggest that Uhrf1 regulates GC B cell proliferation and affinity maturation, and its expression in GC B cells is required for virus clearance.
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Schwickert, Tanja A., Gabriel D. Victora, David R. Fooksman, Alice O. Kamphorst, Monica R. Mugnier, Alexander D. Gitlin, Michael L. Dustin, and Michel C. Nussenzweig. "A dynamic T cell–limited checkpoint regulates affinity-dependent B cell entry into the germinal center." Journal of Experimental Medicine 208, no. 6 (May 16, 2011): 1243–52. http://dx.doi.org/10.1084/jem.20102477.
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The germinal center (GC) reaction is essential for the generation of the somatically hypermutated, high-affinity antibodies that mediate adaptive immunity. Entry into the GC is limited to a small number of B cell clones; however, the process by which this limited number of clones is selected is unclear. In this study, we demonstrate that low-affinity B cells intrinsically capable of seeding a GC reaction fail to expand and become activated in the presence of higher-affinity B cells even before GC coalescence. Live multiphoton imaging shows that selection is based on the amount of peptide–major histocompatibility complex (pMHC) presented to cognate T cells within clusters of responding B and T cells at the T–B border. We propose a model in which T cell help is restricted to the B cells with the highest amounts of pMHC, thus allowing for a dynamic affinity threshold to be imposed on antigen-binding B cells.
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Phan, Ryan T., Khang Nguyen, Sonia Romero, Alice Nicolson, Phillipp Nham, and Dany V. Nguyen. "A Germinal Center- Derived B Cell Lymphoma Model." Blood 116, no. 21 (November 19, 2010): 2008. http://dx.doi.org/10.1182/blood.v116.21.2008.2008.
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Abstract Abstract 2008 Most human B-cell lymphomas represent mature phenotypes of germinal center (GC) or post-GC origin and are frequently associated with chromosomal translocations, often involving the rearrangement of immunoglobulin (Ig) loci to various cellular oncogenes, leading to oncogenic activation. The mechanisms underlying these processes, however, are not well understood. Several studies suggest that these genetic lesions arise from errors of physiologic DNA rearrangements in GC B cells, namely class switch recombination (CSR) and somatic hypermutation (SHM). Here we report the generation of a mouse model in which DNA breaks are physiologically instituted in mature B cells, yet inefficiently repaired via specific deletion of DNA repair gene XRCC4 in GC B cells, thus effectively creating an in vivo environment for errors in DNA rearrangements. These activated B cells exhibit significant increased chromosomal IgH locus breaks and reduced CSR. In p53-deficient background, these mice develop B-cell lymphoma from 5.5 to 16 months. These clonally developed tumors characteristically harbor chromosomal translocations and phenotypically resemble mature phenotypes. Many of these tumors bear mutated V genes, suggesting that those cells have transited through GC. Thus, this mouse model mimics human B-cell lymphoma and might be useful for the development of therapeutic interventions in B-cell lymphoma. Disclosures: No relevant conflicts of interest to declare.
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Bentebibel, Salah-Eddine, Nathalie Schmitt1, Rimpei Morita, Jacques Banchereau, and Hideki Ueno. "Human T follicular helper cells comprise subsets specialized for help of distinct B cell subsets (99.9)." Journal of Immunology 184, no. 1_Supplement (April 1, 2010): 99.9. http://dx.doi.org/10.4049/jimmunol.184.supp.99.9.
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Abstract T follicular helper cells (Tfh) represent a Th subset specialized for the help of antibody responses. In contrast to recent progress regarding the phenotype and developmental mechanism of Tfh cells, how Tfh cells regulate B cell responses is less well characterized. In particular, whether Tfh cells are involved in the differentiation of naïve B cells into antibody-secreting cells (ASCs) remains largely unknown. Here we show that human tonsillar Tfh cells comprise subsets specialized for the help of distinct B cell subsets. A subset of Tfh cells, here called Pre-Tfh cells, is specialized for the help of naïve B cells. In contrast, Tfh cells at germinal centers (GC-Tfh cells) are the only Tfh subset able to induce germinal center B (GC-B) cells to produce Igs. Despite the capacity to secrete high levels of Interleukin-21 (IL-21), Pre-Tfh cells failed to help GC-B cells, due to the induction of apoptosis of GC-B cells via FAS/FAS ligand interaction. While Pre-Tfh cells were found exclusively at extrafollicular sites, Pre-Tfh cells expressed Bcl6, a master transcription factor of Tfh cells, at equivalent levels with GC-Tfh cells. A comprehensive gene expression profiling strongly suggests that pre-Tfh cells are progenitors of GC-Tfh cells. Thus, the differentiation of functional human Tfh cells already occurs at outside of B cell follicles, and such extrafollicular Tfh cells are engaged in the differentiation of naïve B cells.
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Joshi, Indira D., and Mitchell R. Smith. "Birinapant Enhances Bendamustine-Induced Apoptosis In Activated B Cell-Diffuse Large Cell Lymphoma Cells." Blood 122, no. 21 (November 15, 2013): 5150. http://dx.doi.org/10.1182/blood.v122.21.5150.5150.
Full textAbstract:
Abstract Birinapant (TL32711), a Smac mimetic in clinical testing, potently targets Inhibitor of Apoptosis Proteins (IAPs, including cIAPs and XIAP) to unblock intrinsic and extrinsic pathways, enabling caspase-dependent apoptosis via multiple signals. Birinapant also inactivates canonical NF-kB signaling through cIAPs. We investigated the pro-apoptotic effects of birinapant, alone and in combination with bendamustine (BDM), an active lymphoma therapeutic agent, in a panel of B cell lymphoma cell lines representing germinal center/follicular (GC) vs. activated B cell (ABC) subtypes. We hypothesized that the efficacy of this potential combination therapeutic strategy might differ between GC and ABC lymphoma types, as ABC are reported to be NF-kB-dependent. We used the following EBV negative cell lines: WSU-FSCCL t(14:18)+ follicular lymphoma (FL), FC-TxFL2 t(14:18)+ transformed FL, and SU-DHL4 GC-type diffuse large B cell lymphoma (DLBCL) as examples of GC origin lymphomas. U2932 and TMD8 cell lines represent ABC-type DLBCL. Apoptosis was determined by annexin V staining and confirmed by caspase-3 activation, each assessed by flow cytometric methods following 48 h incubation. Birinapant had little effect (<5% annexin V+ cells) as a single agent on any of these B cell lymphoma cell lines at ≤ 100 nM, though a low level of apoptosis (7-12% annexin V+ cells) was detectable at 10-20 µM in GC types. Addition of birinapant 30-60 minutes prior to BDM did not further enhance the already high level (>50% annexin V+) of apoptosis induced by 10 uM BDM in WSU-FSCCL and FC-TxFL2, and only slightly enhanced the low level of BDM-induced apoptosis in the GC DLBCL cell line DHL-4 (to 10-15%). In the ABC DLBCL cell lines, however, whereas 10uM BDM induced <5% annexin V+ cells for U2932 and 10-15% for TMD8, addition of 100 nM birinapant 30-60 minutes prior to 10 uM BDM induced 35-40% annexin V+ cells in each of these ABC-DLBCL cell lines. This enhancement was schedule-dependent, not observed when birinapant was added after BDM. Thus, the cell lines representing FL and transformed FL are sensitive to BDM at clinically-achievable concentrations, without further enhancement by birinapant. The 3 DLBCL lines were relatively insensitive to BDM compared with FL cells, but BDM-induced apoptosis was markedly enhanced when birinapant was added before (but not after) BDM in the 2 ABC type DLBCL lines. Further explorations into the mechanism of birinapant sensitization of ABC-DLBCL to BDM, issues of dose and schedule, and role of NF-kB-dependency are ongoing. These data suggest that therapeutic trials of BDM plus birinapant would be of interest in ABC type DLBCL. Disclosures: No relevant conflicts of interest to declare.
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Wray-Dutra, Michelle N., Raghav Chawla, Kerri R. Thomas, Brenda J. Seymour, Tanvi Arkatkar, Karen M. Sommer, Socheath Khim, Cole Trapnell, Richard G. James, and David J. Rawlings. "Activated CARD11 accelerates germinal center kinetics, promoting mTORC1 and terminal differentiation." Journal of Experimental Medicine 215, no. 9 (August 20, 2018): 2445–61. http://dx.doi.org/10.1084/jem.20180230.
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Activating mutations in the adapter protein CARD11 associated with diffuse large B cell lymphomas (DLBCLs) are predicted to arise during germinal center (GC) responses, leading to inappropriate activation of NF-κB signaling. Here, we modeled the B cell–intrinsic impact of the L251P activating mutation in CARD11 (aCARD11) on the GC response. Global B cell aCARD11 expression led to a modest increase in splenic B cells and a severe reduction in B1 B cell numbers, respectively. Following T cell–dependent immunization, aCARD11 cells exhibited increased rates of GC formation, resolution, and differentiation. Restriction of aCARD11 to GC B cells similarly altered the GC response and B cell differentiation. In this model, aCARD11 promoted dark zone skewing along with increased cycling, AID levels, and class switch recombination. Furthermore, aCard11 GC B cells displayed increased biomass and mTORC1 signaling, suggesting a novel strategy for targeting aCARD11-driven DLBCL. While aCARD11 potently impacts GC responses, the rapid GC contraction suggests it requires collaboration with events that limit terminal differentiation to promote lymphoma.
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Zotos, Dimitra, Jonathan M. Coquet, Yang Zhang, Amanda Light, Kathy D'Costa, Axel Kallies, Lynn M. Corcoran, et al. "IL-21 regulates germinal center B cell differentiation and proliferation through a B cell–intrinsic mechanism." Journal of Experimental Medicine 207, no. 2 (February 8, 2010): 365–78. http://dx.doi.org/10.1084/jem.20091777.
Full textAbstract:
Germinal centers (GCs) are sites of B cell proliferation, somatic hypermutation, and selection of variants with improved affinity for antigen. Long-lived memory B cells and plasma cells are also generated in GCs, although how B cell differentiation in GCs is regulated is unclear. IL-21, secreted by T follicular helper cells, is important for adaptive immune responses, although there are conflicting reports on its target cells and mode of action in vivo. We show that the absence of IL-21 signaling profoundly affects the B cell response to protein antigen, reducing splenic and bone marrow plasma cell formation and GC persistence and function, influencing their proliferation, transition into memory B cells, and affinity maturation. Using bone marrow chimeras, we show that these activities are primarily a result of CD3-expressing cells producing IL-21 that acts directly on B cells. Molecularly, IL-21 maintains expression of Bcl-6 in GC B cells. The absence of IL-21 or IL-21 receptor does not abrogate the appearance of T cells in GCs or the appearance of CD4 T cells with a follicular helper phenotype. IL-21 thus controls fate choices of GC B cells directly.
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Moser, Emily K., Jennifer Roof, Joseph Dybas, Lynn Spruce, Stephen Seeholzer, Michael P. Cancro, and Paula M. Oliver. "The E3 Ubiquitin Ligase Itch Restricts the Magnitude of Antigen-Driven B Cell responses." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 218.1. http://dx.doi.org/10.4049/jimmunol.204.supp.218.1.
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Abstract More than 23 million Americans suffer from autoimmune disease, driven in large part by germinal center (GC)-derived autoantibodies. In GC B cells, somatic hypermutation of immunoglobulin (Ig) genes can render autoreactivity, but cells bearing autoreactive Ig receptors are eliminated due to strict selection of GC B cells by mechanisms that are still poorly defined. The E3 ubiquitin ligase Itch prevents the emergence of autoimmune disease and autoantibodies in humans and mice, and patients lacking Itch develop debilitating, multi-faceted, potentially fatal, autoimmune disease; yet how Itch regulates GC B cell fate or function has not previously been explored. By studying spontaneous and immunization-induced GC B cell responses in Itch deficient mice, we now show that Itch directly limits B cell activity to shape antibody responses. While Itch-deficient mice displayed normal numbers of pre-immune B cell populations, they showed elevated numbers of antigen-experienced B cells. Mixed bone marrow chimeras revealed that Itch acts within B cells to limit follicular and GC B cell numbers. Proteomic profiling of acutely activated B cells uncovered that Itch limited abundance of a subset of proteins involved in cell cycle and mTORC1 activity. We next found that B cells lacking Itch showed increased proliferation, glycolytic capacity, and mTORC1 activation in vitro and in vivo. Moreover, stimulation of these cells by in vivo immunization resulted in elevated numbers of GC B cells, plasma cells, and serum IgG. These results support a novel role for Itch in limiting B cell metabolism and proliferation to suppress GC B cell responses, supporting the idea that overly-exuberant GC B cell responses may contribute to autoimmunity in Itch deficiency.
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Taylor, Justin J., Kathryn A. Pape, and Marc K. Jenkins. "A germinal center–independent pathway generates unswitched memory B cells early in the primary response." Journal of Experimental Medicine 209, no. 3 (February 27, 2012): 597–606. http://dx.doi.org/10.1084/jem.20111696.
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Memory B cells can be produced from the classical germinal center (GC) pathway or a less understood GC-independent route. We used antigen-based cell enrichment to assess the relative contributions of these pathways to the polyclonal memory B cell pool. We identified a CD38+ GL7+ B cell precursor population that differentiated directly into IgM+ or isotype-switched (sw) Ig+ memory B cells in a GC-independent fashion in response to strong CD40 stimulation. Alternatively, CD38+ GL7+ B cell precursors had the potential to become Bcl-6+ GC cells that then generated primarily swIg+ memory B cells. These results demonstrate that early IgM+ and swIg+ memory B cells are products of a GC-independent pathway, whereas later switched Ig+ memory B cells are products of GC cells.
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Glazier, Kim S., Sandra B. Hake, Helen M. Tobin, Amy Chadburn, Elaine J. Schattner, and Lisa K. Denzin. "Germinal Center B Cells Regulate Their Capability to Present Antigen by Modulation of HLA-DO." Journal of Experimental Medicine 195, no. 8 (April 15, 2002): 1063–69. http://dx.doi.org/10.1084/jem.20012059.
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Peptide acquisition by MHC class II molecules is catalyzed by HLA-DM (DM). In B cells, HLA-DO (DO) inhibits or modifies the peptide exchange activity of DM. We show here that DO protein levels are modulated during B cell differentiation. Remarkably, germinal center (GC) B cells, which have low levels of DO relative to naive and memory B cells, are shown to have enhanced antigen presentation capabilities. DM protein levels also were somewhat reduced in GC B cells; however, the ratio of DM to DO in GC B cells was substantially increased, resulting in more free DM in GC B cells. We conclude that modulation of DM and DO in distinct stages of B cell differentiation represents a mechanism by which B cells regulate their capacity to function as antigen-presenting cells. Efficient antigen presentation in GC B cells would promote GC B cell–T cell interactions that are essential for B cells to survive positive selection in the GC.
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Domeier, Phillip P., Sathi Babu Chodisetti, Chetna Soni, Stephanie L. Schell, Melinda J. Elias, Daisuke Kitamura, and Ziaur Rahman. "Interferon-γ receptor and STAT1 signaling in B cells are central to spontaneous germinal center formation and autoimmunity." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 47.9. http://dx.doi.org/10.4049/jimmunol.196.supp.47.9.
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Abstract In Systemic Lupus Erythematosus (SLE), spontaneously developed germinal centers (Spt-GCs) harbor AutoAb-producing B cells that promote disease, but the mechanisms that control Spt-GC development are not clear. Here we report that B cell-intrinsic IFNγR and STAT1 signaling are essential for Spt-GC formation. The IFNγR deficiency, however, does not significantly affect foreign Ag-induced GC and Tfh responses, suggesting that two distinct mechanisms regulate foreign-Ag vs Spt-GC responses. We also demonstrate that IFNγR-mediated STAT1 signaling drives T-bet expression, pro-GC gene expression and IFNγ production by B cells, which are critical for Spt-GC and Tfh development. To understand how IFNγ signaling regulates the Spt-GC response and associated AutoAb production in SLE, we utilized B6.Sle1b mice that harbor the lupus-prone NZM2410 strain-derived SLAM locus. B6.Sle1b mice exhibit elevated Spt-GC and follicular helper T cell (Tfh) responses that associate with impaired B cell selection in GCs. B6.Sle1b mice with B cell intrinsic IFNγR deficiency have significantly reduced Spt-GC and Tfh responses resulting in a markedly lower number of IgG-producing antibody forming cells and diminished IgG2c and IgG2b autoantibody titers compared to B6.Sle1b mice. Additionally, the proliferation and differentiation of DNA-reactive B cells into a GC B cell phenotype require B cell-intrinsic IFNγR signaling. Together, our data define a novel B cell-intrinsic IFNγR signaling pathway in Spt-GC development and autoimmunity.
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Ramachandrareddy, Himabindu, Yulei Shen, Wing C. Chan, and Timothy W. McKeithan. "Epigenetic regulation of BCL6 and other genes important for B-cell maturation (136.32)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 136.32. http://dx.doi.org/10.4049/jimmunol.182.supp.136.32.
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Abstract BCL6, a proto-oncogene frequently mutated and translocated in B-cell lymphoma, encodes a transcriptional repressor essential for the germinal center (GC) reaction. BCL6 mRNA and protein have higher expression in GC-B cells than in pre- and post-GC-B cells despite strong autorepression. Hypothesizing that histone modifications epigenetically regulate BCL6 during B-cell differentiation, we mapped a number of histone modifications associated with active transcription far upstream to the promoters of BCL6 and ~100 other genes in pre-GC-B, GC-B and plasma cell lines at nucleosomal resolution using the ChIP-chip assay. We identified numerous regions of histone H3 acetylation and H3 lysine-4 mono- and trimethylation (H3K4me1 and -3) within and upstream of BCL6; most striking was a vast region of H3K4me1 extending 140-260 kb upstream of BCL6 seen in a GC-B-cell line, but not in pre- or post-GC-B-cells. We also observed high expression of an intergenic transcript within this far upstream region in GC-B-cell lines but not in numerous other lines, suggesting distant regulatory regions, active only in GC-B-cells, account for high BCL6 expression. Many other genes also showed evidence for stage-specific distal regulatory regions. Defining a histone code for B cell master regulators will elucidate transcriptional networks central to both the immune response and cancer. The work is supported by UNMC Eppley Cancer Institute.
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Zheng, Biao, Guiliang Xu, Xi Chen, Ekaterina Marinova, and Shuhua Han. "ICOSL-mediated signaling is essential for the survival and functional maturation of germinal center B cells through the classical NF-κB pathway (IRM10P.611)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 131.9. http://dx.doi.org/10.4049/jimmunol.194.supp.131.9.
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Abstract The molecular mechanisms by which helper T-cells support B-cell activation, survival and functional differentiation in the germinal center (GC) are not well-defined. To date, signaling through CD40 by CD40L is the only established receptor-ligand signaling pathway initiated by helper T-cells. Here we show that helper T-cells provide helper signal to B-cells through the inducible T-cell co-stimulator (ICOS)-ICOS ligand (ICOSL) interaction. We found that reverse ICOSL signaling on GC B-cells is essential and sufficient to promote GC B-cell survival and functional maturation; whereas CD40-mediated signaling plays a minor role during GC reaction, although critical in initiating the GC response. In vivo ICOSL engagement by ICOS-Ig fusion protein can rescue impaired GC formation and antibody production in ICOS-deficient mice. Various lines of ICOSL mutant mice, including pan-B cell-specific ICOSL-deficient mice, GC B cell-specific ICOSL-deficient mice, and ICOSL intra-cellular domain mutant mice, all show defective humoral response and impaired GC reaction. ICOSL reverse signaling in GC B cells is dependent on activation of the classical NF-kB signal pathway, resulting in increased BCL2, c-MYC and FOXO1 expression that supports GC B cell survival and differentiation. Thus, CD40-CD40L interaction mainly supports the initiation of GC response, whereas ICOS-ICOSL collaboration provides bi-directional signals that support the maintenance and functional maturation of GC B cells.
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Pinschewer, Daniel D., Bénédict Fallet, Yi Hao, Marianna Florova, Karen Cornille, Alba Verge de los Aires, Giulia Girelli Zubani, et al. "Chronic viral infection promotes efficient germinal center B cell responses." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 247.4. http://dx.doi.org/10.4049/jimmunol.204.supp.247.4.
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Abstract Persistent viral infections subvert key elements of adaptive immunity. To compare germinal center (GC) B cell responses in chronic and acute lymphocytic choriomeningitis virus infection we exploit activation-induced deaminase (AID) fate-reporter mice and perform adoptive B cell transfer experiments. Chronic infection yields GC B cell responses of higher cellularity than acute infection, higher memory B cell and antibody secreting cell output for longer periods of time, a better representation of the late B cell repertoire in serum immunoglobulin and higher titers of protective neutralizing antibodies. GC B cells of chronically infected mice are similarly hypermutated as those emerging from acute infection. They efficiently adapt to viral escape variants and even in hypermutation-impaired AID-mutant mice, chronic infection selects for GC B cells with hypermutated BCRs and neutralizing antibody formation. These findings demonstrate that, unlike for CD8+ T cells, chronic viral infection drives a functional, productive and protective GC B cell response.
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Dawod, Muath, Juan Gomez-Gelvez, Ahmad Mattour, Kedar V. Inamdar, and Nalini Janakiraman. "Prognostic Significance of Cell of Origin Subclassification in Diffuse Large B Cell Lymphoma." Blood 120, no. 21 (November 16, 2012): 5081. http://dx.doi.org/10.1182/blood.v120.21.5081.5081.
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Abstract Abstract 5081 Background: Diffuse large B cell lymphoma (DLBCL) is a heterogeneous disease that has been divided into three different prognostic subgroups: Germinal Center B cell-like (GC), Activated B cell-like (ABC) and type 3 according to gene expression profile using cDNA. Immunohistochemistry (IHC) has been used as surrogate to identify these cell-of-origin subgroups. Data about the prognostic value of IHC has been conflicting. Patients and methods: In this retrospective study, we reviewed the charts of 252 patients diagnosed with DLBCL at Henry Ford Hospital from 1999 to 2012. We excluded patients with HIV, transformed lymphomas and unavailable samples. Data was collected on a total of 157 patients. The following data was gathered: age, sex, race, IPI score, disease stage, hemoglobin, white blood and platelet counts, best response achieved and dates of treatment start, relapse, death or last follow up. Tissue microarray slides with the following IHC stains (CD10, MUM1, Bcl6) were prepared and reviewed when needed. Using Hans Algorithm, samples were divided into two major groups (GC-like and non-GC-like). 3-year progression free and overall survivals were compared between all subgroups using a log-rank test. Continuous variables were reported as median and range, and compared using Wilcoxon rank-sum tests. Categorical variables were reported as median and range, and compared using Chi-square tests. Statistical significance was set at p<0. 05. Results: Eighty patients (51%) were classified as GC-like, and 77 patients (49%) as non-GC-like. GC-like subgroup had a significantly longer 3-year progression free survival (90% vs 74%, P=0. 024), as compared with the non-GC-like subgroup. There was a trend toward longer overall survival but it didn't reach statistical significance (74% vs 67%, P=0. 161). For all patients, IPI stands as a strong prognostic index with 3-year overall survival of (85% and 46%, P=<. 001) in patients with low IPI (0 to 2) and high IPI (3 to 5) respectively. Interestingly, in patients with low IPI, cell of origin stands as a prognostic factor with 3-year progression free survival of (96% and 81%, P=0. 032) in GC-like and non-GC-like groups respectively. While in patients with high IPI, there was no significant difference in progression free survival in cell-of-origin subgroups. Conclusion: Cell of origin subclassification as determined by IHC surrogate markers predict for better progression free survival in GC-like subgroup but not for overall survival. While this prognostic value was maintained in patients with low IPI, there was no prognostic significance in patients with high IPI. IPI is still a valuable prognostic tool in patients with DLBCL. Disclosures: No relevant conflicts of interest to declare.
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Stedra, J., and J. Cerny. "Distinct pathways of B cell differentiation. I. Residual T cells in athymic mice support the development of splenic germinal centers and B cell memory without an induction of antibody." Journal of Immunology 152, no. 4 (February 15, 1994): 1718–26. http://dx.doi.org/10.4049/jimmunol.152.4.1718.
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Abstract B cell memory to T cell-dependent Ags develops in the germinal centers (GC). Here we report that thymus-deficient, nu/nu mice immunized with phosphorylcholine coupled to keyhole limpet hemocyanin (EPC-KLH) develop GC in the spleen in the absence of Ab-forming cell (AFC) response. However, the formation of GC on EPC-KLH immunization requires T cells, because 1) CB.1.7-scid mice reconstituted with B lymphocytes failed to develop GC without a supplement of CD4+ cells and 2) in vivo administration of an anti-CD4 mAb abolished the GC response in euthymic mice. Thus, it appears that the formation of GC in nu/nu mice was due to a low number of T cells that were detectable in situ within the splenic lymphoid follicles. The numbers of GC in individual Ag-stimulated nu/nu mice appeared to correlate with the density of T cells in the splenic sections. The B cells in these GC expressed T15, the dominant Id of anti-PC Ab, and became primed for an anamnestic response. Secondary challenge with EPC-KLH resulted in an increased number of GC without detectable AFC. However, when the Ag-primed nu/nu mice received CD4+ lymphocytes 1 day before the challenge, they demonstrated a vigorous AFC response that was predominantly IgM and significantly higher than the secondary response of nu/nu mice that had been reconstituted with CD4+ cells during both primary and secondary immunizations. Therefore, it appears that immunization of nu/nu mice may lead to an early step of B cell activation and memory development even though the T lymphocytes in these mice are incompetent to provide help for Ab formation. The memory and Ab pathways of B cell differentiation may involve different mechanisms of T cell help.
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Domeier, Phillip P., Sathi Babu Chodisetti, Chetna Soni, Stephanie L. Schell, Melinda J. Elias, Eric B. Wong, Timothy K. Cooper, Daisuke Kitamura, and Ziaur S. M. Rahman. "IFN-γ receptor and STAT1 signaling in B cells are central to spontaneous germinal center formation and autoimmunity." Journal of Experimental Medicine 213, no. 5 (April 11, 2016): 715–32. http://dx.doi.org/10.1084/jem.20151722.
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Spontaneously developed germinal centers (GCs [Spt-GCs]) harbor autoreactive B cells that generate somatically mutated and class-switched pathogenic autoantibodies (auto-Abs) to promote autoimmunity. However, the mechanisms that regulate Spt-GC development are not clear. In this study, we report that B cell–intrinsic IFN-γ receptor (IFN-γR) and STAT1 signaling are required for Spt-GC and follicular T helper cell (Tfh cell) development. We further demonstrate that IFN-γR and STAT1 signaling control Spt-GC and Tfh cell formation by driving T-bet expression and IFN-γ production by B cells. Global or B cell–specific IFN-γR deficiency in autoimmune B6.Sle1b mice leads to significantly reduced Spt-GC and Tfh cell responses, resulting in diminished antinuclear Ab reactivity and IgG2c and IgG2b auto-Ab titers compared with B6.Sle1b mice. Additionally, we observed that the proliferation and differentiation of DNA-reactive B cells into a GC B cell phenotype require B cell–intrinsic IFN-γR signaling, suggesting that IFN-γR signaling regulates GC B cell tolerance to nuclear self-antigens. The IFN-γR deficiency, however, does not affect GC, Tfh cell, or Ab responses against T cell–dependent foreign antigens, indicating that IFN-γR signaling regulates autoimmune, but not the foreign antigen–driven, GC and Tfh cell responses. Together, our data define a novel B cell–intrinsic IFN-γR signaling pathway specific to Spt-GC development and autoimmunity. This novel pathway can be targeted for future pharmacological intervention to treat systemic lupus erythematosus.
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Zaretsky, Irina, Ofir Atrakchi, Roei D. Mazor, Liat Stoler-Barak, Adi Biram, Sara W. Feigelson, Alexander D. Gitlin, Britta Engelhardt, and Ziv Shulman. "ICAMs support B cell interactions with T follicular helper cells and promote clonal selection." Journal of Experimental Medicine 214, no. 11 (September 22, 2017): 3435–48. http://dx.doi.org/10.1084/jem.20171129.
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The germinal center (GC) reaction begins with a diverse and expanded group of B cell clones bearing a wide range of antibody affinities. During GC colonization, B cells engage in long-lasting interactions with T follicular helper (Tfh) cells, a process that depends on antigen uptake and antigen presentation to the Tfh cells. How long-lasting T–B interactions and B cell clonal expansion are regulated by antigen presentation remains unclear. Here, we use in vivo B cell competition models and intravital imaging to examine the adhesive mechanisms governing B cell selection for GC colonization. We find that intercellular adhesion molecule 1 (ICAM-1) and ICAM-2 on B cells are essential for long-lasting cognate Tfh–B cell interactions and efficient selection of low-affinity B cell clones for proliferative clonal expansion. Thus, B cell ICAMs promote efficient antibody immune response by enhancement of T cell help to cognate B cells.
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Kwak, Kihyuck, Avva Saniee, Nicolas Quizon, Haewon Sohn, and Susan Pierce. "Extraction and intracellular trafficking of membrane associated antigen distinguishes human germinal center B cells from naïve B cells and memory B cells." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 99.25. http://dx.doi.org/10.4049/jimmunol.200.supp.99.25.
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Abstract Protective antibody responses to vaccination or infection in humans depend on the competitive selection of high-affinity germinal-center (GC) B cells into the long-lived memory B cell compartment. Selection is determined in large part by the ability of GC B cells to gather, process and present antigen to T follicular helper T cells (TFH cells). We have shown that human GC B cells are better able to distinguish their affinity for antigen as compared to naïve B cells in the gathering and internalization of antigen. Here we provide evidence that human naïve B cells and GC B cells rely on different endocytic processes for antigen internalization and trafficking. We found that the Microtubule Organizing Centers in activated GC B cells were not polarized toward the immune synapse with the antigen-containing membrane as in naïve B cells but rather dispersed large distances from the immune synapse in GC B cells. GC B cells trafficked antigen-bound BCRs from the synapse outside the sides of the cells to distal sites for internalization whereas naïve B cells internalized antigen from the immune synapse. Moreover, as compared to naïve B cells, LAMP-1+ vesicles in GC B cells were less polarized and less internalized antigen was colocalized with LAMP-1+ vesicles. We also found that the expression of SNX9 and SNX18, key components of the endocytosis machinery and modulators of clathrine mediated endocytosis, was significantly lower in GC B cells as compared to naïve B cells and SNX9 and SNX18 were poorly polarized toward the immune synapse in activated GC B cells. We propose that these differences in endocytosis processes for antigen internalization contribute the higher affinity thresholds of GC B cells.
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Parthasarathy, Raksha, Jennifer Yates, Thomas Hagglof, Elizabeth A. Dudley, and Elizabth Leadbetter. "Leveraging iNKT cells to identify signals driving B cell memory commitment." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 55.02. http://dx.doi.org/10.4049/jimmunol.208.supp.55.02.
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Abstract Intense scrutiny of the process of memory B cells (MBC) over the last decade has improved our understanding of MBC development especially for vaccines against viruses capable of rapid diversification like SARS-CoV-2. Most memory responses develop in germinal centers (GC), but the constellation of specific signals which commit B cells to a memory fate is poorly understood. Identification of discrete T and B cell factors leading to MBC commitment is hindered by a lack of murine models with essential controls. We report a unique system harnessing iNKT cell help for B cells to create two conditions, both of which expand NP+ B cells in a class-switched primary response, but only one of which produces a MBC response. In the first case, NP+ B cells receive exclusive cognate iNKT cells upon immunization with the Nitrophenyl-haptenated iNKT cell agonist alphaGalactosylCeramide (NP-aGC) leading to an expansion of NP+ GC B cells, but not MBCs. In contrast, NP+ B cells helped by conventional T cells adjuvanted by iNKT cell activation by vaccinating with haptenated protein (NP-KLH) plus aGC drives a conventional GC B cell expansion and development of NP+ MBCs. Interestingly, cognate antigen which does not induce B memory also elicits fewer pre-memory B cells, compared to non-cognate antigen. These different immunization regimens allow a unique comparison of activated B cells recognizing identical epitopes and producing similar primary humoral responses but with contrasting memory outcomes. Importantly, this also controls for the GC environment which is unaccounted for in other model systems. Examination of these B cell populations will better define the transcriptional landscape of MBC and pinpoint key signals which dictate MBC fate. Supported by AAI Careers in Immunology Fellowship 2021
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Lagresle, C., C. Bella, P. T. Daniel, P. H. Krammer, and T. Defrance. "Regulation of germinal center B cell differentiation. Role of the human APO-1/Fas (CD95) molecule." Journal of Immunology 154, no. 11 (June 1, 1995): 5746–56. http://dx.doi.org/10.4049/jimmunol.154.11.5746.
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Abstract We previously described the existence of a tonsillar IgD- B cell subset with memory B cell features. To test the possibility that these cells could derive from germinal center (GC) B cell precursors, we examined the proliferation, differentiation, and phenotype of GC B cells after culturing with either anti-CD40 Abs or activated T cells, presumably mimicking the signals received by centrocytes in the light zone of GC. We show in this work that GC B cells proliferate and secrete Igs in both activation systems, thus indicating that CD40 ligation is also required for differentiation of GC B cells along the plasmacytoid pathway. T cell-dependent activation of GC B cells induced down-regulation of most GC-related markers (CD10, CD38, and CD77) and up-regulation of CD44 and CD62-L which are both expressed on the putative memory B cells subset. Moreover, T cell-mediated stimulation of GC B cells resulted in the strong induction of CD5 and up-regulation of APO-1/Fas (CD95). In contrast, stimulation performed with immobilized anti-CD40 Abs did not affect expression of CD10 and CD38 and failed to induce CD62-L and CD5, suggesting that the CD40 signaling pathway is necessary but not sufficient for the development of memory B cells. CD95 ligation on GC B cells was found to antagonize the stimulatory effect of immobilized anti-CD40 Abs on their proliferation, survival, and Bcl-2 expression. The possible role of CD95 in the expansion and selection of the Ag-activated B cell clones in GC is discussed.
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Grigorova, Irina, Zachary Benet, and Fang Ke. "Dissecting the role of proinflammatory chemokine CCL3 in the selection of germinal center B cells and in secondary antibody responses." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 121.15. http://dx.doi.org/10.4049/jimmunol.202.supp.121.15.
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Abstract Expression of CCL3 and CCL4 chemokines is upregulated in B cells upon crosslinking of B cell receptors and in germinal center (GC) centrocytes. However, the role of these proinflammatory chemokines in B cell responses is still unclear. Single cell qPCR analysis suggests that only a small fraction of GC centrocytes upregulates expression of CCL3/4. While B cell-intrinsic production of CCL3 promotes B cell interactions and negative control by follicular regulatory T cells at the peak of GC response, at the later stages of GC response it promotes B cells selection. Consistent with that, secondary antibody responses in CCL3 knockout mice are reduced. Our findings suggest that CCL3 is involved into multifaceted regulation of GC responses. Analyses of the mechanisms promoting both the negative and positive regulation of GC B cells in CCL3-dependent fashion are underway. These studies should be important for dissecting the role of CCL3 in normal immune responses and in B cell-originated lymphomas, where CCL3/4 are often elevated.
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Dutra, Michelle N., Brenda Seymour, Karen Sommer, Richard James, and David Rawlings. "Modeling altered germinal center responses due to oncogenic activating mutations in CARMA1." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 142.17. http://dx.doi.org/10.4049/jimmunol.196.supp.142.17.
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Abstract BCR engagement drives phosphorylation of the multi-adapter, CARMA1, and assembly of signaling complexes required for NF-κB activation. B cell lymphomas are frequently associated with constitutive NF-κB activation that sustains their survival. At least 10% of germinal center (GC) derived, activated B-cell like diffuse large B-cell lymphomas (ABC-DLBCLs) exhibit gain-of-function mutations in CARMA1. In the current study, we directly assess the impact activated CARMA1 (aCARMA1) on GC biology. We developed a novel mouse model that permits inducible expression of aCARMA1. Following T-dependent immunization, mice with B cell intrinsic aCARMA1 exhibit an expanded plasma cell compartment and reduced GC B cell numbers. A similar phenotype was present with GC restricted aCARMA1 expression, leading to increased total and antigen-specific IgG. ABC-DLBCL tumors frequently exhibit somatic mutations predicted to block terminal B cell differentiation. To better define how aCARMA1 impacts GC biology and cooperates with these lesions, we crossed KI mice to Blimp1F/F mice. aCARMA1 expression, in the absence of Blimp1, lead to increased GC B cell numbers compared to controls. Current studies are focused on detailed analysis of this altered response. Our results demonstrate that aCARMA1 is sufficient to alter the GC response and B cell fate, favoring plasma cell development. Further, in the setting of inability to exit the GC, aCARMA1 may be sufficient to directly promote lymphomagenesis.