scholarly journals Receptor Interacting Protein Kinase Pathways Regulate Innate B Cell Developmental Checkpoints But Not Effector Function in Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Raksha Parthasarathy ◽  
Thomas Hägglöf ◽  
Jason T. Hadley ◽  
Alexandra McLennan ◽  
Aiden Mattke ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Fate ◽  
Cell Types ◽  
Effector Function ◽  
Caspase 8 ◽  
B Cell Differentiation ◽  
Autoantibody Production ◽  
Interacting Protein ◽  
Cell Commitment

Mutations in the scaffolding domain of Receptor Interacting Protein kinases (RIP) underlie the recently described human autoimmune syndrome, CRIA, characterized by lymphadenopathy, splenomegaly, and autoantibody production. While disease mechanisms for CRIA remain undescribed, RIP kinases work together with caspase-8 to regulate cell death, which is critical for normal differentiation of many cell types. Here, we describe a key role for RIP1 in facilitating innate B cell differentiation and subsequent activation. By comparing RIP1, RIP3, and caspase-8 triple deficient and RIP3, caspase-8 double deficient mice, we identified selective contributions of RIP1 to an accumulation of murine splenic Marginal Zone (MZ) B cells and B1-b cells. We used mixed bone-marrow chimeras to determine that innate B cell commitment required B cell-intrinsic RIP1, RIP3, and caspase-8 sufficiency. RIP1 regulated MZ B cell development rather than differentiation and RIP1 mediates its innate immune effects independent of the RIP1 kinase domain. NP-KLH/alum and NP-Ficoll vaccination of mice doubly deficient in both caspase-8 and RIP3 or deficient in all three proteins (RIP3, caspase-8, and RIP1) revealed uniquely delayed T-dependent and T-independent IgG responses, abnormal splenic germinal center architecture, and reduced extrafollicular plasmablast formation compared to WT mice. Thus, RIP kinases and caspase-8 jointly orchestrate B cell fate and delayed effector function through a B cell-intrinsic mechanism.

scholarly journals Intracellular sterol sensing controls intestinal B cell differentiation

2020 ◽  
Author(s):  
Bruno C. Trindade ◽  
Simona Ceglia ◽  
Alyssa Berthelette ◽  
Fiona Raso ◽  
Kelsey Howley ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Fate ◽  
Plasma Cells ◽  
Cell Metabolism ◽  
Dietary Cholesterol ◽  
Effector Function ◽  
B Cell Differentiation ◽  
Environmental Signals ◽  
Iga Response

AbstractIntestinal B cell responses are critical for the maintenance of gut homeostasis, yet environmental signals that control B cell metabolism and effector function remain poorly characterized. Here, we show that Peyer’s patches germinal center (GC) B cells are sensitive to 25-hydroxycholesterol (25-HC), an oxidized metabolite of cholesterol produced by the enzyme cholesterol 25-hydroxylase (CH25H). In mice lacking CH25H, antigen-specific GC B cells show an increased cholesterol metabolic signature and preferentially differentiate in plasma cells (PCs), thereby inducing a stronger intestinal IgA response upon immunization or infection. GC B cells express the sterol sensor SREBP2 and use it to sense 25-HC. Deletion of SREBP2 from GC B cells prevents PC differentiation and forces the maintenance of GC identity. GC localized oxysterol production by follicular dendritic cells is central in dictating GC metabolism and imposing B cell fate. Our findings show that the 25-HC-SREBP2 axis shapes B cell effector function in intestinal lymphoid organs and indicate that dietary cholesterol can instruct local B cell response.

scholarly journals Restriction of memory B cell differentiation at the germinal center B cell positive selection stage

2020 ◽  
Vol 217 (7) ◽  
Author(s):  
Amparo Toboso-Navasa ◽  
Arief Gunawan ◽  
Giulia Morlino ◽  
Rinako Nakagawa ◽  
Andrea Taddei ◽  
...  
Keyword(s):  
B Cells ◽  
Positive Selection ◽  
B Cell ◽  
Cell Fate ◽  
Germinal Center ◽  
Target Genes ◽  
Zinc Finger Protein ◽  
B Cell Differentiation ◽  
Repressor Complex ◽  
Selection Stage

Memory B cells (MBCs) are key for protection from reinfection. However, it is mechanistically unclear how germinal center (GC) B cells differentiate into MBCs. MYC is transiently induced in cells fated for GC expansion and plasma cell (PC) formation, so-called positively selected GC B cells. We found that these cells coexpressed MYC and MIZ1 (MYC-interacting zinc-finger protein 1 [ZBTB17]). MYC and MIZ1 are transcriptional activators; however, they form a transcriptional repressor complex that represses MIZ1 target genes. Mice lacking MYC–MIZ1 complexes displayed impaired cell cycle entry of positively selected GC B cells and reduced GC B cell expansion and PC formation. Notably, absence of MYC–MIZ1 complexes in positively selected GC B cells led to a gene expression profile alike that of MBCs and increased MBC differentiation. Thus, at the GC positive selection stage, MYC–MIZ1 complexes are required for effective GC expansion and PC formation and to restrict MBC differentiation. We propose that MYC and MIZ1 form a module that regulates GC B cell fate.

scholarly journals Essential role of EBF1 in the generation and function of distinct mature B cell types

2012 ◽  
Vol 209 (4) ◽  
pp. 775-792 ◽  
Author(s):  
Bojan Vilagos ◽  
Mareike Hoffmann ◽  
Abdallah Souabni ◽  
Qiong Sun ◽  
Barbara Werner ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Intracellular Signaling ◽  
Ectopic Expression ◽  
Cell Types ◽  
Cell Development ◽  
B Cell Development ◽  
Cell Stage ◽  
Cell Immunity ◽  
Cell Commitment

The transcription factor EBF1 is essential for lineage specification in early B cell development. In this study, we demonstrate by conditional mutagenesis that EBF1 is required for B cell commitment, pro–B cell development, and subsequent transition to the pre–B cell stage. Later in B cell development, EBF1 was essential for the generation and maintenance of several mature B cell types. Marginal zone and B-1 B cells were lost, whereas follicular (FO) and germinal center (GC) B cells were reduced in the absence of EBF1. Activation of the B cell receptor resulted in impaired intracellular signaling, proliferation and survival of EBF1-deficient FO B cells. Immune responses were severely reduced upon Ebf1 inactivation, as GCs were formed but not maintained. ChIP- and RNA-sequencing of FO B cells identified EBF1-activated genes that encode receptors, signal transducers, and transcriptional regulators implicated in B cell signaling. Notably, ectopic expression of EBF1 efficiently induced the development of B-1 cells at the expense of conventional B cells. These gain- and loss-of-function analyses uncovered novel important functions of EBF1 in controlling B cell immunity.

scholarly journals VLA-4 Expression and Activation in B Cell Malignancies: Functional and Clinical Aspects

2020 ◽  
Vol 21 (6) ◽  
pp. 2206 ◽  
Author(s):  
Andrea Härzschel ◽  
Antonella Zucchetto ◽  
Valter Gattei ◽  
Tanja Nicole Hartmann
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Types ◽  
Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Clinical Aspects ◽  
Neoplastic Disease ◽  
B Cell Differentiation ◽  
B Cell Malignancies ◽  
Bcr Signaling

Lineage commitment and differentiation of hematopoietic cells takes place in well-defined microenvironmental surroundings. Communication with other cell types is a vital prerequisite for the normal functions of the immune system, while disturbances in this communication support the development and progression of neoplastic disease. Integrins such as the integrin very late antigen-4 (VLA-4; CD49d/CD29) control the localization of healthy as well as malignant B cells within the tissue, and thus determine the patterns of organ infiltration. Malignant B cells retain some key characteristics of their normal counterparts, with B cell receptor (BCR) signaling and integrin-mediated adhesion being essential mediators of tumor cell homing, survival and proliferation. It is thus not surprising that targeting the BCR pathway using small molecule inhibitors has proved highly effective in the treatment of B cell malignancies. Attenuation of BCR-dependent lymphoma–microenvironment interactions was, in this regard, described as a main mechanism critically contributing to the efficacy of these agents. Here, we review the contribution of VLA-4 to normal B cell differentiation on the one hand, and to the pathophysiology of B cell malignancies on the other hand. We describe its impact as a prognostic marker, its interplay with BCR signaling and its predictive role for novel BCR-targeting therapies, in chronic lymphocytic leukemia and beyond.

Notch Activation Converts B Cells into a T Cell Fate at the Earliest Stages of B Cell Committed Progenitors.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3151-3151
Author(s):  
Jalal Taneera ◽  
Emma Smith ◽  
Mikael Sigvardsson ◽  
Emil Hansson ◽  
Urban Lindahl ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Fate ◽  
T Cell Development ◽  
Cell Development ◽  
Cell Stage ◽  
Cell Commitment ◽  
Notch Activation

Abstract Notch activation has been suggested to promote T cell development at the expense of B cell commitment at the level of a common lymphoid progenitor prior to B cell commitment. Here, we explored the possibility that Notch activation might be able to switch the fate of already committed B cell progenitors towards T cell development upon Notch activation. To address this we overexpressed constitutively activated Notch-3 (N3IC) in B cell progenitors purified from transgenic mice in which human CD25 is expressed under control of the λ5 promoter. Strikingly, whereas untransduced and control transduced B220+λ5+CD3− B cell progenitors gave rise exclusively to B cells, CD4+ and CD8+ T cells but no B cells were derived from N3IC-transduced cells when transplanted into sublethally irradiated NOD-SCID mice. Gene expression profiling demonstrated that untransduced B220+ λ5+CD3− B cell progenitors expressed λ5 and CD19 but not the T cell specific genes GATA-3, lck and pTα, whereas CD3+ T cells derived from N3IC-transduced B220+λ5+CD3−cells failed to express λ5 and CD19, but were positive for GATA-3, lck and pTα expression as well as a and b T cell rearrangement. Furthermore, DJ rearrangements were detected at very low levels in CD3+ cells isolated from normal non-transduced BM, but were more abundant in the N3IC-transduced CD3+ BM cells. Noteworthy, N3IC-transduced B220+λ5+CD3−CD19+ proB cell progenitors failed to generate B as well as T cells, whereas N3IC-transduced B220+λ5+CD3−CD19− pre-proB cells produced exclusively T cells, even when evaluated at low cell numbers. In conclusion Notch activation can switch committed B cell progenitors from a B cell to a T cell fate, but this plasticity is lost at the Pro-B cell stage, upon upregulation of CD19 expression.

scholarly journals Atypical chemokine receptor 4 shapes activated B cell fate

2018 ◽  
Vol 215 (3) ◽  
pp. 801-813 ◽  
Author(s):  
Ervin E. Kara ◽  
Cameron R. Bastow ◽  
Duncan R. McKenzie ◽  
Carly E. Gregor ◽  
Kevin A. Fenix ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Fate ◽  
Chemokine Receptor ◽  
Cell Trafficking ◽  
B Cell Differentiation ◽  
Cell Responses ◽  
Early Memory ◽  
Chemokine Receptor 4 ◽  
Activated B Cells

Activated B cells can initially differentiate into three functionally distinct fates—early plasmablasts (PBs), germinal center (GC) B cells, or early memory B cells—by mechanisms that remain poorly understood. Here, we identify atypical chemokine receptor 4 (ACKR4), a decoy receptor that binds and degrades CCR7 ligands CCL19/CCL21, as a regulator of early activated B cell differentiation. By restricting initial access to splenic interfollicular zones (IFZs), ACKR4 limits the early proliferation of activated B cells, reducing the numbers available for subsequent differentiation. Consequently, ACKR4 deficiency enhanced early PB and GC B cell responses in a CCL19/CCL21-dependent and B cell–intrinsic manner. Conversely, aberrant localization of ACKR4-deficient activated B cells to the IFZ was associated with their preferential commitment to the early PB linage. Our results reveal a regulatory mechanism of B cell trafficking via an atypical chemokine receptor that shapes activated B cell fate.

scholarly journals Tissue-Resident PSGL1loCD4+ T Cells Interact with B Cells Via PD-1 and PD-L2 in Gvhd Target Tissues to Augment Autoimmune-like Chronic Gvhd

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5607-5607
Author(s):  
Xiaohui Kong ◽  
Deye Zeng ◽  
Xiwei Wu ◽  
Shijie Yang ◽  
Bixin Wang ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Research Funding ◽  
Cellular Therapy ◽  
Chronic Gvhd ◽  
Advisory Board ◽  
Murine Models ◽  
B Cell Differentiation ◽  
Autoantibody Production

Chronic graft versus host disease (cGVHD) is a systemic autoimmune-like syndrome, and donor-type CD4+ T interaction with B cells plays an important role in its pathogenesis. Our recent publication has demonstrated that cGVHD pathogenesis does not require germinal center formation and is associated with expansion of extrafollicular CD44hiCD62LloPSGL1loCD4+ (PSGL1loCD4+) T cells in the spleen and GVHD target tissues. The causal role of PSGL1loCD4+ T cells in cGVHD pathogenesis remains unclear. With murine and humanized murine models, we show that both murine and human PSGL1loCD4+ T cells reside in tissues and do not circulate in the blood, and their high expression of PD-1 and ICOS and production of IL-21 suggest that they provide B cell help. In murine models, PSGL1loCD4+ T cells augment plasma cell expansion and autoantibody production via their PD-1 interaction with PD-L2 on B. In humanized mouse models, human PSGL1loCD4+ T cells from GVHD target tissues augment memory B cell differentiation into plasma cells and antibody production via their production of IL-21.These results indicate that tissue-resident PSGL1loCD4+ T cells augment autoantibody production and cGVHD pathogenesis. Targeting tissue-resident T cells may represent a novel approach for treating cGVHD. Disclosures Nakamura: Alexion: Other: support to a lecture at a Japan Society of Transfusion/Cellular Therapy meeting ; Kirin Kyowa: Other: support for an academic seminar in a university in Japan; Celgene: Other: support for an academic seminar in a university in Japan; Merck: Membership on an entity's Board of Directors or advisory committees. Martin:Abgenomics: Research Funding; Enlivex Therapeutics: Consultancy; Genentech: Consultancy, Other: One-time advisory board; Neovii: Other: One-time advisory board; Pfizer: Other: Data and Safety Monitoring Committee; Pharmacyclics LLC: Other: One-time advisory board; Procter and Gamble: Equity Ownership; Xenikos: Research Funding.

Regulation and Function of NOTCH2 in B-CLL Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1138-1138
Author(s):  
Rainer Hubmann ◽  
Martin Hilgarth ◽  
Susanne Schnabl ◽  
Dita Demirtas ◽  
Josef D. Schwarzmeier ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Fate ◽  
Target Gene ◽  
Active Form ◽  
Lymphocytic Leukemia ◽  
B Cell Differentiation ◽  
Cell Fate Decisions ◽  
Mutational Status ◽  
And Function

Abstract B-cell chronic lymphocytic leukemia (B-CLL) represents a clonal expansion of self-reactive CD5+ B-lymphocytes which seems to be resistant to apoptosis in vivo. One of the characteristics of B-CLL lymphocytes is the high expression of the B-cell differentiation/activation marker CD23 which we recently identified as a target gene for NOTCH2 signaling. NOTCH2 is implicated in the development/homeostasis of murine CD5+ (B-1a) B-cells, suggesting a function for human NOTCH2 in B-CLL leukemogenesis. Here we show that peripheral B-CLL lymphocytes overexpress a transcriptionally active form of NOTCH2 (N2IC) irrespective of their prognostic marker profile (ie. IgVH mutational status, CD38 expression, and cytogenetics). Although the majority of unstimulated B-CLL samples downregulate their N2IC activity in vitro, DNA-bound N2IC complexes could be maintained by the protein kinase C (PKC) activator TPA (12-O-tetradecanoylphorbol 13-acetate) accompanied by an upregulation of the NOTCH2 target gene CD23 and increased B-CLL cell viability. These effects are sensitive to the PKC-δ selective inhibitor Rottlerin. In 80% of B-CLL cases, NOTCH2 signaling was found to be resistant to the γ-secretase inhibitors (GSI’s) Dapt and compound E, indicative for the expression of truncated forms of NOTCH2 which do not require γ-secretase for processing and function. Inhibition of NOTCH2 either by Dapt in GSI sensitive B-CLL cases or, more specifically, by RNA interference downregulates CD23 expression on the mRNA and protein level and sensitizes B-CLL cells for apoptosis. Since self-reactive B-cells are normally eliminated either by chronic (anergy) or apoptotic (negative selection) B-cell receptor (BCR) signaling, we asked whether NOTCH2 modulates B-cell fate decisions triggered by the BCR. For this reason, we stably transduced the human B-cell line BL41 with constitutive active forms of NOTCH2 and found that NOTCH2 inhibits BCR mediated apoptosis induced by surface-IgM cross-linking. In summary, the data demonstrate that NOTCH2 signaling is deregulated in B-CLL cells and might be critically involved in the PKC-dependent maintenance of their malignant phenotype.

scholarly journals Specific hypomethylation programs underpin B cell activation in early multiple sclerosis

2021 ◽  
Vol 118 (51) ◽  
pp. e2111920118
Author(s):  
Qin Ma ◽  
Stacy J. Caillier ◽  
Shaun Muzic ◽  
Michael R. Wilson ◽  
Roland G. Henry ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
Cell Function ◽  
Immune Cell ◽  
Disease Onset ◽  
Cell Types ◽  
B Cell Differentiation ◽  
Dna Hypomethylation

Epigenetic changes have been consistently detected in different cell types in multiple sclerosis (MS). However, their contribution to MS pathogenesis remains poorly understood partly because of sample heterogeneity and limited coverage of array-based methods. To fill this gap, we conducted a comprehensive analysis of genome-wide DNA methylation patterns in four peripheral immune cell populations isolated from 29 MS patients at clinical disease onset and 24 healthy controls. We show that B cells from new-onset untreated MS cases display more significant methylation changes than other disease-implicated immune cell types, consisting of a global DNA hypomethylation signature. Importantly, 4,933 MS-associated differentially methylated regions in B cells were identified, and this epigenetic signature underlies specific genetic programs involved in B cell differentiation and activation. Integration of the methylome to changes in gene expression and susceptibility-associated regions further indicates that hypomethylated regions are significantly associated with the up-regulation of cell activation transcriptional programs. Altogether, these findings implicate aberrant B cell function in MS etiology.

scholarly journals Autoreactive T cells preferentially drive differentiation of non-responsive memory B cells at the expense of germinal center maintenance

2018 ◽  
Author(s):  
Rajiv W Jain ◽  
Kate A Parham ◽  
Yodit Tesfagiorgis ◽  
Heather C Craig ◽  
Emiliano Romanchik ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Fate ◽  
Germinal Center ◽  
Memory B Cells ◽  
B Cell Differentiation ◽  
Cell Fate Decisions ◽  
The Status

AbstractB cell fate decisions within a germinal center (GC) are critical to determining the outcome of the immune response to a given antigen. Here, we characterize GC kinetics and B cell fate choices in a response to the autoantigen myelin oligodendrocyte glycoprotein (MOG), and compare them the response to a standard model foreign antigen (NP-haptenated ovalbumin, NPOVA). Both antigens generated productive primary responses, as evidenced by GC development, circulating antigen-specific antibodies, and differentiation of memory B cells. However, in the MOG response the status of the cognate T cell partner drove preferential B cell differentiation to a memory phenotype at the expense of GC maintenance, resulting in a truncated GC. Reduced plasma cell differentiation was largely independent of T cell influence. Interestingly, memory B cells formed in the MOG GC were unresponsive to secondary challenge and this could not be overcome with T cell help.

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