Over‐expression of p190Rho GEF enhances B‐cell activation and germinal center formation in T‐cell‐dependent humoral immune responses

2019 ◽  
Vol 97 (10) ◽  
pp. 877-887 ◽  
Author(s):  
Ji Hye Jeong ◽  
Yun Jung Ha ◽  
So‐Yeon Choi ◽  
Jee‐Hae Kim ◽  
Yungdae Yun ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
B Cell ◽  
Germinal Center ◽  
Cell Activation ◽  
B Cell Activation ◽  
Over Expression ◽  
Humoral Immune ◽  
Humoral Immune Responses ◽  
Germinal Center Formation

scholarly journals Essential Function for the Nuclear Protein Akirin2 in B Cell Activation and Humoral Immune Responses

2015 ◽  
Vol 195 (2) ◽  
pp. 519-527 ◽  
Author(s):  
Sarang Tartey ◽  
Kazufumi Matsushita ◽  
Tomoko Imamura ◽  
Atsuko Wakabayashi ◽  
Daisuke Ori ◽  
...  
Keyword(s):  
Immune Responses ◽  
B Cell ◽  
Cell Activation ◽  
Nuclear Protein ◽  
B Cell Activation ◽  
Humoral Immune ◽  
Humoral Immune Responses ◽  
Essential Function

scholarly journals TRAF6 Is Required for Generation of the B-1a B Cell Compartment as well as T Cell-Dependent and -Independent Humoral Immune Responses

PLoS ONE ◽  
2009 ◽  
Vol 4 (3) ◽  
pp. e4736 ◽  
Author(s):  
Takashi Kobayashi ◽  
Tae Soo Kim ◽  
Anand Jacob ◽  
Matthew C. Walsh ◽  
Yuho Kadono ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
B Cell ◽  
Cell Compartment ◽  
Humoral Immune ◽  
Humoral Immune Responses

CD154:CD40 Co-Stimulatory Blockade: A Novel Approach To Prevent Sensitization to Donor Alloantigens.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1273-1273
Author(s):  
Hong Xu ◽  
Jun Yan ◽  
Suzanne T. Ildstad
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
B Cell ◽  
Germinal Center ◽  
Cell Activation ◽  
Cell Tolerance ◽  
B Cell Activation ◽  
B Cell Tolerance ◽  
Adaptive Immune Responses ◽  
Adaptive Immune

Abstract Introduction: Recipient sensitization is one of the most critical problems facing clinical transplantation. Allosensitized recipients often rapidly reject vascularized solid organ grafts as a result of preformed anti-donor antibody. Similarly, bone marrow transplantation for sickle cell disease and thalassemia is limited by sensitization from transfusion. A method to prevent sensitization would have a significant impact on transplant outcomes. Until recently, T cells were believed to be the primary effector cell in the induction of adaptive immune responses. We recently found that humoral immunity provides a dominant barrier in allosensitization to MHC antigens. B cell activation occurs through T-cell-dependent responses via signaling from the co-stimulatory molecule CD154 (on T cells) to its ligand CD40 (on B cells). Here, we examined whether blocking the costimulatory interaction between T and B cells during exposure to alloantigen would prevent allosensitization. Materials and Methods: Mice deficient for CD154 molecule (CD154−/ −, H-2b), α β-TCR+ T cells (TCRβ −/ −, H-2b); or wild type B6 (H-2b) mice received allogeneic BALB/c (H-2d) skin grafts (SG) on day 0. Some B6 mice were also treated with anti-CD154 (day0 and day+3) and/or anti-α β-TCR mAb (day-3) peritransplant. Antibodies were detected by flow cytometry cross-match (FCM) assay and reported as mean fluorescence intensity (MFI). Results: CD154−/ − mice rejected primary BALB/c SG with a time course similar to normal B6 controls (12.4 ± 2.1 vs. 12.7 ± 2.4 days). TCRβ −/ − mice accepted SG permanently (>120 days). Notably, anti-donor antibody was not generated in either the CD154−/ − or TCRβ −/ − mice (MFI: 4.1 ± 0.1 and 4.2 ± 0.4) after SG compared with Ab in naïve serum (3.0±0.2). Sensitized B6 mice had significantly higher antibody titers (106.8 ± 35.1) 4 weeks after SG rejection. A second SG transplanted 5 to 7 weeks after the first graft was rejected at an accelerated rate (9.0 ± 0.8 days, P < 0.05) in the CD154−/ − mice, but no anti-donor MHC antibody was produced. Second grafts placed on TCRβ −/ − mice were accepted, as were the primary SG. In normal B6 recipients pretreated with anti-CD154 or anti-α β-TCR alone, SG survival was not significantly prolonged. The Ab titers were only slightly higher in mice treated with anti-CD154 (5.9±3.4; P>0.05) than in naïve mice, and significantly higher in mice treated with mAb anti-α β-TCR (45.1±25.6; P=0.03). The combined treatment with both mAbs resulted in complete abrogation of Ab production (4.2±0.9) and 70% of skin grafts survived >100 days. Germinal center formation, reflective of B cell activation, was completely disrupted in mice treated with anti-CD154 alone or combined with anti-α β-TCR. Conclusion: These results suggest that the CD40/CD154 co-stimulatory pathway is critically important in B cell activation to generate alloantibody. Notably, blocking molecular interactions between CD40/CD154 abrogated the generation of antibody and blocked germinal center formation, inducing B cell tolerance. The additional removal of recipient T cells in the context of co-stimulatory blockade resulted in the induction of T as well as B cell tolerance. These findings are the first demonstration that sensitization can be prevented through blockade of co-stimulatory interactions in the generation of adaptive immune responses and could have a significant impact on management of sensitized recipients in the clinic.

scholarly journals The in vivo function of a noncanonical TRAF2-binding domain in the C-terminus of CD40 in driving B-cell growth and differentiation

Blood ◽  
2007 ◽  
Vol 110 (1) ◽  
pp. 193-200 ◽  
Author(s):  
Li-Fan Lu ◽  
Cory L. Ahonen ◽  
Evan F. Lind ◽  
Vanitha S. Raman ◽  
W. James Cook ◽  
...  
Keyword(s):  
Immune Responses ◽  
B Cell ◽  
Cell Activation ◽  
Affinity Maturation ◽  
Functional Domain ◽  
Antibody Isotype ◽  
Humoral Immune ◽  
Humoral Immune Responses ◽  
Cell Immunity

The recruitment of tumor necrosis factor receptor–associated factors (TRAFs) 1, 2, 3, 5, and 6 to the CD40 cytoplasmic tail upon CD40 trimerization results in downstream signaling events that ultimately lead to CD40-dependent, thymus-dependent (TD) humoral immune responses. Previously, we have shown signaling through the C-terminal tail of CD40 in the absence of canonical TRAF-binding sites is capable of signaling through an alternative TRAF2-binding site. Here, we demonstrate that B cells from mice harboring CD40 with only the C-terminal tail can activate both canonical and noncanonical NFκB signaling pathways. Moreover, while lacking germinal center formation, several hallmarks of humoral immune responses including clonal B-cell activation/expansion, antibody isotype switching, and affinity maturation remain normal. This study demonstrates a new functional domain in CD40 that controls critical aspects of B-cell immunity in an in vivo setting.

Dok-3 plays a nonredundant role in negative regulation of B-cell activation

Blood ◽  
2007 ◽  
Vol 110 (1) ◽  
pp. 259-266 ◽  
Author(s):  
Chee-Hoe Ng ◽  
Shengli Xu ◽  
Kong-Peng Lam
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
Cell Receptor ◽  
Negative Regulation ◽  
Myelogenous Leukemia ◽  
Type I ◽  
B Cell Activation ◽  
Humoral Immune ◽  
Humoral Immune Responses

p62dok and Dok-3 are members of the Dok family of adaptors found in B cells, with the former cloned as a substrate of the p210bcr/abl oncoprotein in Ph + chronic myelogenous leukemia. A role for p62dok in FcγRIIB–mediated negative regulation of B-cell proliferation had been established previously. Here, we generated Dok-3−/− mice to assess the function of Dok-3 in B cells. Mice lacking Dok-3 have normal B-cell development but possess higher level of IgM antibodies in their sera. In comparison to wild-type mice, Dok-3−/− mice mounted significantly enhanced humoral immune responses to T cell–independent type I and II antigens. Dok-3–deficient B cells hyperproliferated, exhibited elevated level of calcium signaling as well as enhanced activation of NF-κB, JNK, and p38MAPK in response to B-cell receptor (BCR) engagement. In the absence of Dok-3, the localization of the inhibitory phosphatase SHIP-1 to the plasma membrane is intact while its phosphorylation is compromised, suggesting that Dok-3 could function to facilitate or sustain the activation of SHIP-1. The phenotype and responses of Dok-3−/− mice and B cells could be differentiated from those of the Dok-1−/− counterparts. Hence, we propose that Dok-3 plays a distinct and nonredundant role in the negative regulation of BCR signaling.

scholarly journals Brg1 Supports B Cell Proliferation and Germinal Center Formation Through Enhancer Activation

2021 ◽  
Vol 12 ◽  
Author(s):  
Dominik Schmiedel ◽  
Hadas Hezroni ◽  
Amit Hamburg ◽  
Ziv Shulman
Keyword(s):  
Gene Expression ◽  
Cell Proliferation ◽  
B Cells ◽  
B Cell ◽  
Transcriptional Activation ◽  
Germinal Center ◽  
Cell Activation ◽  
Critical Role ◽  
B Cell Activation ◽  
Germinal Center Formation

Activation and differentiation of B cells depend on extensive rewiring of gene expression networks through changes in chromatin structure and accessibility. The chromatin remodeling complex BAF with its catalytic subunit Brg1 was previously identified as an essential regulator of early B cell development, however, how Brg1 orchestrates gene expression during mature B cell activation is less clear. Here, we find that Brg1 is required for B cell proliferation and germinal center formation through selective interactions with enhancers. Brg1 recruitment to enhancers following B cell activation was associated with increased chromatin accessibility and transcriptional activation of their coupled promoters, thereby regulating the expression of cell cycle-associated genes. Accordingly, Brg1-deficient B cells were unable to mount germinal center reactions and support the formation of class-switched plasma cells. Our findings show that changes in B cell transcriptomes that support B cell proliferation and GC formation depend on enhancer activation by Brg1. Thus, the BAF complex plays a critical role during the onset of the humoral immune response.

scholarly journals Recombinant Rabies Virus Overexpressing OX40-Ligand Enhances Humoral Immune Responses by Increasing T Follicular Helper Cells and Germinal Center B Cells

Vaccines ◽  
2020 ◽  
Vol 8 (1) ◽  
pp. 144 ◽  
Author(s):  
Yingying Li ◽  
Ling Zhao ◽  
Baokui Sui ◽  
Zhaochen Luo ◽  
Yachun Zhang ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
Immune Responses ◽  
Rabies Virus ◽  
Germinal Center ◽  
Rabies Vaccine ◽  
Humoral Immune ◽  
Humoral Immune Responses ◽  
Follicular Helper ◽  
Ox40 Ligand

Rabies, caused by the rabies virus (RABV), remains a serious threat to public health in most countries. Development of a single-dose and efficacious rabies vaccine is the most important method to restrict rabies virus transmission. Costimulatory factor OX40-ligand (OX40L) plays a crucial role in the T cell-dependent humoral immune responses through T-B cell interaction. In this work, a recombinant RABV overexpressing mouse OX40L (LBNSE-OX40L) was constructed, and its effects on immunogenicity were evaluated in a mouse model. LBNSE-OX40L-immunized mice generated a larger number of T follicular helper (Tfh) cells, germinal center (GC) B cells, and plasma cells (PCs) than the parent virus LBNSE-immunized mice. Furthermore, LBNSE-OX40L induced significantly higher levels of virus-neutralizing antibodies (VNA) as early as seven days post immunization (dpi), which lasted for eight weeks, resulting in better protection for mice than LBNSE (a live-attenuated rabies vaccine strain). Taken together, our data in this study suggest that OX40L can be a novel and potential adjuvant to improve the induction of protective antibody responses post RABV immunization by triggering T cell-dependent humoral immune responses, and that LBNSE-OX40L can be developed as an efficacious and nonpathogenic vaccine for animals.

scholarly journals The Toll-like Receptor Protein Rp105 Regulates Lipopolysaccharide Signaling in B Cells

2000 ◽  
Vol 192 (1) ◽  
pp. 23-30 ◽  
Author(s):  
Hirotaka Ogata ◽  
I-hsin Su ◽  
Kensuke Miyake ◽  
Yoshinori Nagai ◽  
Sachiko Akashi ◽  
...  
Keyword(s):  
B Cells ◽  
Immune Responses ◽  
B Cell ◽  
Neutralizing Antibodies ◽  
Cell Activation ◽  
Nuclear Factor Κb ◽  
Receptor Protein ◽  
B Cell Activation ◽  
Toll Like Receptor ◽  
Humoral Immune

The susceptibility to infections induced by Gram-negative bacteria is largely determined by innate immune responses to bacteria cell wall lipopolysaccharide (LPS). The stimulation of B cells by LPS enhances their antigen-presenting capacity and is accompanied by B cell proliferation and secretion of large quantities of LPS-neutralizing antibodies. Similar to macrophages and neutrophils, the LPS-induced activation of B cells is dependent on Toll-like receptor (TLR)4. Here, we demonstrate that the responses of B cells to LPS are also regulated by another TLR protein, RP105, which is predominantly expressed on mature B cells in mice and humans. The analysis of mice homozygous for the null mutation in the RP105 gene revealed impaired proliferative and humoral immune responses of RP105-deficient B cells to LPS. Using originally LPS-unresponsive Ba/F3 cells expressing exogenous TLR4 and RP105, we demonstrate the functional cooperation between TLR4 and RP105 in LPS-induced nuclear factor κB activation. These data suggest the existence of the TLR4–RP105 signaling module in the LPS-induced B cell activation.

scholarly journals B cell ADAM17 controls T cell independent humoral immune responses through regulation of TACI and CD138

2020 ◽  
Vol 522 (2) ◽  
pp. 442-447
Author(s):  
Joseph C. Lownik ◽  
Jessica L. Wimberly ◽  
Leila Takahashi-Ruiz ◽  
Rebecca K. Martin
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
B Cell ◽  
Humoral Immune ◽  
Humoral Immune Responses
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