scholarly journals A critical role of TAK1 in B-cell receptor–mediated nuclear factor κB activation

Blood ◽  
2009 ◽  
Vol 113 (19) ◽  
pp. 4566-4574 ◽  
Author(s):  
James Schuman ◽  
Yuhong Chen ◽  
Andrew Podd ◽  
Mei Yu ◽  
Hong-Hsing Liu ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Critical Role ◽  
Cell Receptor ◽  
Nuclear Factor Κb ◽  
Cell Development ◽  
B Cell Receptor ◽  
Nuclear Factor

Abstract The kinase TAK1 is essential for T-cell receptor (TCR)–mediated nuclear factor κB (NF-κB) activation and T-cell development. However, the role of TAK1 in B-cell receptor (BCR)–mediated NF-κB activation and B-cell development is not clear. Here we show that B-cell–specific deletion of TAK1 impaired the transition from transitional type 2 to mature follicular (FO) B cells and caused a marked decrease of marginal zone (MZ) B cells. TAK1-deficient B cells exhibited an increase of BCR-induced apoptosis and impaired proliferation in response to BCR ligation. Importantly, TAK1-deficient B cells failed to activate NF-κB after BCR stimulation. Thus, TAK1 is critical for B-cell maturation and BCR-induced NF-κB activation.

scholarly journals Essential Role of Phospholipase Cγ2 in Early B-Cell Development and Myc-Mediated Lymphomagenesis

2006 ◽  
Vol 26 (24) ◽  
pp. 9364-9376 ◽  
Author(s):  
Renren Wen ◽  
Yuhong Chen ◽  
Li Bai ◽  
Guoping Fu ◽  
James Schuman ◽  
...  
Keyword(s):  
B Cells ◽  
Transgenic Mice ◽  
B Cell ◽  
Cell Receptor ◽  
Cell Development ◽  
B Cell Development ◽  
B Cell Receptor ◽  
Wild Type ◽  
Interleukin 7

ABSTRACT Phospholipase Cγ2 (PLCγ2) is a critical signaling effector of the B-cell receptor (BCR). Here we show that PLCγ2 deficiency impedes early B-cell development, resulting in an increase of B220+ CD43+ BP-1+ CD24hi pre-BCR+ large pre-B cells. PLCγ2 deficiency impairs pre-BCR-mediated functions, leading to enhanced interleukin-7 (IL-7) signaling and elevated levels of RAGs in the selected large pre-B cells. Consequently, PLCγ2 deficiency renders large pre-B cells susceptible to transformation, resulting in dramatic acceleration of Myc-induced lymphomagenesis. PLCγ2 −/− Eμ-Myc transgenic mice mainly develop lymphomas of B220+ CD43+ BP-1+ CD24hi pre-BCR+ large pre-B-cell origin, which are uncommon in wild-type Eμ-Myc transgenics. Furthermore, lymphomas from PLCγ2 −/− Eμ-Myc transgenic mice exhibited a loss of p27Kip1 and often displayed alterations in Arf or p53. Thus, PLCγ2 plays an important role in pre-BCR-mediated early B-cell development, and its deficiency leads to markedly increased pools of the most at-risk large pre-B cells, which display hyperresponsiveness to IL-7 and express high levels of RAGs, making them prone to secondary mutations and Myc-induced malignancy.

scholarly journals B-Cell Receptor- and Phorbol Ester-Induced NF-κB and c-Jun N-Terminal Kinase Activation in B Cells Requires Novel Protein Kinase C's

2001 ◽  
Vol 21 (19) ◽  
pp. 6640-6650 ◽  
Author(s):  
Daniel Krappmann ◽  
Alina Patke ◽  
Vigo Heissmeyer ◽  
Claus Scheidereit
Keyword(s):  
B Cells ◽  
Protein Kinase ◽  
B Cell ◽  
Phorbol Ester ◽  
Critical Role ◽  
Ectopic Expression ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Novel Protein

ABSTRACT Antigen receptor signaling is known to activate NF-κB in lymphocytes. While T-cell-receptor-induced NF-κB activation critically depends on novel protein kinase C θ (PKCθ), the role of novel PKCs in B-cell stimulation has not been elucidated. In primary murine splenic B cells, we found high expression of the novel PKCs δ and ɛ but only weak expression of the θ isoform. Rottlerin blocks phorbol ester (phorbol myristate acetate [PMA])- or B-cell receptor (BCR)-mediated NF-κB and c-Jun N-terminal kinase (JNK) activation in primary B and T cells to a similar extent, suggesting that novel PKCs are positive regulators of signaling in hematopoietic cells. Mouse 70Z/3 pre-B cells have been widely used as a model for NF-κB activation in B cells. Similar to the situation in splenic B cells, rottlerin inhibits BCR and PMA stimulation of NF-κB in 70Z/3 cells. A derivative of 70Z/3 cells, 1.3E2 cells, are defective in NF-κB activation due to the lack of the IκB kinase (IKKγ) protein. Ectopic expression of IKKγ can rescue NF-κB activation in response to lipopolysaccharides (LPS) and interleukin-1β (IL-1β), but not to PMA. In addition, PMA-induced activation of the mitogen-activated protein kinase JNK is blocked in 1.3E2 cells, suggesting that an upstream component common to both pathways is either missing or mutated. Analysis of various PKC isoforms revealed that exclusively PKCθ was absent in 1.3E2 cells while it was expressed in 70Z/3 cells. Stable expression of either novel PKCθ or -δ but not classical PKCβII in 1.3E2 IKKγ-expressing cells rescues PMA activation of NF-κB and JNK signaling, demonstrating a critical role of novel PKCs for B-cell activation.

MALT1 directs B cell receptor–induced canonical nuclear factor-κB signaling selectively to the c-Rel subunit

2007 ◽  
Vol 8 (9) ◽  
pp. 984-991 ◽  
Author(s):  
Uta Ferch ◽  
Christian Meyer zum Büschenfelde ◽  
Andreas Gewies ◽  
Elmar Wegener ◽  
Sandra Rauser ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Receptor ◽  
Nuclear Factor Κb ◽  
B Cell Receptor ◽  
Nuclear Factor

#630 Role of the pre-B cell receptor complex in B cell development

1998 ◽  
Vol 20 (4) ◽  
pp. 383
Author(s):  
S. R. Rheingold ◽  
M. Jiang ◽  
S. A. Grupp ◽  
B. Himelstein
Keyword(s):  
B Cell ◽  
Cell Receptor ◽  
Cell Development ◽  
B Cell Development ◽  
B Cell Receptor ◽  
Receptor Complex

Characterisation of B Cell Receptor-Induced NF-KB Activation In Chronic Lymphocytic Leukaemia Cells

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 375-375 ◽  
Author(s):  
Fatima Talab ◽  
Victoria Thompson ◽  
John C Allen ◽  
Ke Lin ◽  
Joseph R Slupsky
Keyword(s):  
B Cells ◽  
Tyrosine Kinase ◽  
Chronic Lymphocytic Leukaemia ◽  
B Cell ◽  
Cell Cultures ◽  
Lymphocytic Leukaemia ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Nfkb Pathway

Abstract Abstract 375 B cell receptor (BCR) signaling promotes survival of the malignant clone in chronic lymphocytic leukaemia (CLL) through its ability to stimulate NFkB pathway signaling. In lymphoid cells, antigen receptor stimulation of this pathway is achieved by engaging the Carma-1 – Bcl10 – MALT1 (CBM) complex for eventual activation of I-kB kinases (IKKs). In B cells, protein kinase C beta (PKCbeta) is an important mediator of CBM complex activation. However, in CLL cells we found that PKCs do not appear to have a role in BCR-mediated NFkB pathway signaling, despite high expression levels of PKCbeta, because the presence of specific inhibitors of this kinase (LY379196 and bisindolylmaleimide-I) has no effect on the induction of IKK phosphorylation during BCR crosslinking. Examination of CBM complex expression suggests an explanation for this phenomenon; the expression levels of Carma-1 and MALT-1 are largely similar in CLL and normal B cells, but the expression of Bcl10 is much reduced in CLL cells. These findings, taken together with the established role of Bcl10 in the pathway of BCR-induced NFkB activation, suggest that CLL cells may employ a different mechanism to activate this pathway during BCR stimulation. Tyrosine kinases are known to play a role in BCR-induced IKK activation in CLL cells because compounds like dasatinib and PP2 inhibit NFkB pathway activation by BCR. One possible tyrosine kinase is c-Abl because we have shown this protein to be overexpressed in CLL cells, where it plays a role in activation of the NFkB pathway. To investigate the role of c-Abl in BCR-induced IKK activation, we used the inhibitor imatinib and found that the presence of this compound partially inhibited IKK phosphorylation in BCR-stimulated CLL cells. However, imatinib can also inhibit Lck, a T cell-specific src-family tyrosine kinase that is expressed by CLL cells. To differentiate between Lck- and c-Abl-mediated BCR signals we used the specific inhibitor 4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[3,2d] pyrimidin-7-yl-cyclopentane (Lck-i). We found that the presence of this compound in CLL cell cultures undergoing BCR stimulation almost completely inhibited the induction of IKK activation. Investigation of Lck-i specificity revealed this compound did not inhibit either c-Abl or Lyn at the concentration used to inhibit Lck in CLL cell cultures. Further investigation of the effects of Lck-i showed that this compound was also effective in inhibiting BCR-induced activation of the Akt and ERK signaling pathways. Taken together, these data suggest a major role for Lck in BCR-mediated signaling in CLL cells, and question the existing paradigm on the importance of Lyn. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Regulation of B cell fate by chronic activity of the IgE B cell receptor

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Zhiyong Yang ◽  
Marcus J Robinson ◽  
Xiangjun Chen ◽  
Geoffrey A Smith ◽  
Jack Taunton ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Fate ◽  
Plasma Cells ◽  
Cell Receptor ◽  
Culture Conditions ◽  
B Cell Receptor ◽  
Cell Cycles ◽  
T Cell Help

IgE can trigger potent allergic responses, yet the mechanisms regulating IgE production are poorly understood. Here we reveal that IgE+ B cells are constrained by chronic activity of the IgE B cell receptor (BCR). In the absence of cognate antigen, the IgE BCR promoted terminal differentiation of B cells into plasma cells (PCs) under cell culture conditions mimicking T cell help. This antigen-independent PC differentiation involved multiple IgE domains and Syk, CD19, BLNK, Btk, and IRF4. Disruption of BCR signaling in mice led to consistently exaggerated IgE+ germinal center (GC) B cell but variably increased PC responses. We were unable to confirm reports that the IgE BCR directly promoted intrinsic apoptosis. Instead, IgE+ GC B cells exhibited poor antigen presentation and prolonged cell cycles, suggesting reduced competition for T cell help. We propose that chronic BCR activity and access to T cell help play critical roles in regulating IgE responses.

scholarly journals Rapid Emergence of T Follicular Helper and Germinal Center B Cells Following Antiretroviral Therapy in Advanced HIV Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Chun-Shu Wong ◽  
Clarisa M. Buckner ◽  
Silvia Lucena Lage ◽  
Luxin Pei ◽  
Felipe L. Assis ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
Antiretroviral Therapy ◽  
B Cell ◽  
Germinal Center ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Cd4 T Cell ◽  
Follicular Helper ◽  
Cell Counts

Low nadir CD4 T-cell counts in HIV+ patients are associated with high morbidity and mortality and lasting immune dysfunction, even after antiretroviral therapy (ART). The early events of immune recovery of T cells and B cells in severely lymphopenic HIV+ patients have not been fully characterized. In a cohort of lymphopenic (CD4 T-cell count < 100/µL) HIV+ patients, we studied mononuclear cells isolated from peripheral blood (PB) and lymph nodes (LN) pre-ART (n = 40) and 6-8 weeks post-ART (n = 30) with evaluation of cellular immunophenotypes; histology on LN sections; functionality of circulating T follicular helper (cTfh) cells; transcriptional and B-cell receptor profile on unfractionated LN and PB samples; and plasma biomarker measurements. A group of 19 healthy controls (HC, n = 19) was used as a comparator. T-cell and B-cell lymphopenia was present in PB pre-ART in HIV+ patients. CD4:CD8 and CD4 T- and B-cell PB subsets partly normalized compared to HC post-ART as viral load decreased. Strikingly in LN, ART led to a rapid decrease in interferon signaling pathways and an increase in Tfh, germinal center and IgD-CD27- B cells, consistent with histological findings of post-ART follicular hyperplasia. However, there was evidence of cTfh cells with decreased helper capacity and of limited B-cell receptor diversification post-ART. In conclusion, we found early signs of immune reconstitution, evidenced by a surge in LN germinal center cells, albeit limited in functionality, in HIV+ patients who initiate ART late in disease.

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