B Cell receptor directs the activation of NFAT and NF-κB via distinct molecular mechanisms

Antony, Pierre; Petro, James B.; Carlesso, Gianluca; Shinners, Nicholas; Lowe, John; Khan, Wasif N.

doi:10.1016/s0014-4827(03)00338-0

Cited by 50 publications

(44 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…These results demonstrate that BTK and PLC-␥2 are required for BCR-induced production of DAG. They also extend our previous findings, which indicate a requirement for BTK and PLC-␥2 in BCR-directed DAG production in DT40 B cells (34,48).…”

Section: Bcr-induced Dag Production Requires Btk and Plc-␥2supporting

confidence: 90%

“…Purified B cells or B cell subsets were labeled for 6 h with palmitic acid (2.5 Ci/ml), as a fatty acid precursor. Lipid synthesis was monitored in wt, btk Ϫ/Ϫ , and plc-␥2 Ϫ/Ϫ B cells, and the production of DAG was quantified as previously described (34,48). Labeled B cells were washed twice with PBS and stimulated through the BCR with 20 g/ml goat anti-mouse IgM F(abЈ) 2 for the indicated times.…”

Section: B Cell Purification and Transitional B Cell Sortingmentioning

confidence: 99%

“…PLC-␥2 catalyzes the hydrolysis of PIP 2 to produce two lipid second messengers, DAG and inositol 1,4,5-triphosphate (IP 3 ) (41). DAG activates various signaling pathways, including those of PKC and Ras, whereas IP 3 binds to its receptors on the endoplasmic reticulum triggering intracellular calcium (Ca 2ϩ ) release (34,(42)(43)(44). High levels of IP 3 facilitate emptying of the intracellular Ca 2ϩ stores, which signals sustained influx of extracellular Ca 2ϩ via calcium release activated channels (45).…”

mentioning

confidence: 99%

“…Additionally, L-type and L-type-like channels have been implicated in both initial and sustained mobilization of calcium in B cells and B cell lines (46,47). Using DT40 chicken B cells, we recently provided genetic evidence that BTK and PLC-␥2 are necessary for optimal production of DAG upon BCR ligation (34,48). Prior studies have demonstrated that BCR-induced proliferation of mature FoB cells correlated with PIP 2 hydrolysis, intracellular Ca 2ϩ increase, and PKC activation, whereas BCR-induced apoptosis of immature B cells correlated with an increase in intracellular Ca 2ϩ in the relative absence of IP 3 production (49,50).…”

mentioning

confidence: 99%

See 3 more Smart Citations

Transitional B Cell Fate Is Associated with Developmental Stage-Specific Regulation of Diacylglycerol and Calcium Signaling upon B Cell Receptor Engagement

Hoek¹,

Antony²,

Lowe³

et al. 2006

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

Functional peripheral mature follicular B (FoB) lymphocytes are thought to develop from immature transitional cells in a BCR-dependent manner. We have previously shown that BCR cross-linking in vitro results in death of early transitional (T1) B cells, whereas late transitional (T2) B cells survive and display phenotypic characteristics of mature FoB cells. We now demonstrate that diacylglycerol (DAG), a lipid second messenger implicated in cell survival and differentiation, is produced preferentially in T2 compared with T1 B cells upon BCR cross-linking. Consistently, inositol 1,4,5-triphosphate is also produced preferentially in T2 compared with T1 B cells. Unexpectedly, the initial calcium peak appears similar in both T1 and T2 B cells, whereas sustained calcium levels are higher in T1 B cells. Pretreatment with 2-aminoethoxydiphenylborate, an inhibitor of inositol 1,4,5-triphosphate receptor-mediated calcium release, and verapamil, an inhibitor of L-type calcium channels, preferentially affects T1 B cells, suggesting that distinct mechanisms regulate calcium mobilization in each of the two transitional B cell subsets. Finally, BCR-mediated DAG production is dependent upon Bruton’s tyrosine kinase and phospholipase C-γ2, enzymes required for the development of FoB from T2 B cells. These results suggest that calcium signaling in the absence of DAG-mediated signals may lead to T1 B cell tolerance, whereas the combined action of DAG and calcium signaling is necessary for survival and differentiation of T2 into mature FoB lymphocytes.

show abstract

Section: Bcr-induced Dag Production Requires Btk and Plc-␥2supporting

confidence: 90%

Section: B Cell Purification and Transitional B Cell Sortingmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Transitional B Cell Fate Is Associated with Developmental Stage-Specific Regulation of Diacylglycerol and Calcium Signaling upon B Cell Receptor Engagement

Hoek¹,

Antony²,

Lowe³

et al. 2006

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

show abstract

“…NFAT, AP-1, and NF-B are known to be involved in the activation of several T cell proinflammatory cytokine genes, including those encoding IL-2 (44 -46), IFN-␥ (47, 48), and TNF-␣ (45, 49). We and others have demonstrated that CD40-mediated activation of B lymphocytes involves AP-1 (50, 51) and NF-B (31, 52) signaling pathways, and there is evidence of CD40-mediated NFAT activation (51,53). We asked if this is also the case for T cell CD40.…”

Section: The Role Of T Cell Cd40 In Activation Of Cytokine Signaling mentioning

confidence: 93%

A Costimulatory Function for T Cell CD40

Munroe

Bishop

2007

The Journal of Immunology

100

View full text Add to dashboard Cite

CD40 plays a significant role in the pathogenesis of inflammation and autoimmunity. B cell CD40 directly activates cells, which can result in autoantibody production. T cells can also express CD40, with an increased frequency and amount of expression seen in CD4+ T lymphocytes of autoimmune mice, including T cells from mice with collagen-induced arthritis. However, the mechanisms of T cell CD40 function have not been clearly defined. To test the hypothesis that CD40 can serve as a costimulatory molecule on T lymphocytes, CD40+ T cells from collagen-induced arthritis mice were examined in parallel with mouse and human T cell lines transfected with CD40. CD40 served as effectively as CD28 in costimulating TCR-mediated activation, including induction of kinase and transcription factor activities and production of cytokines. An additional enhancement was seen when both CD40 and CD28 signals were combined with AgR stimulation. These findings reveal potent biologic functions for T cell CD40 and suggest an additional means for amplification of autoimmune responses.

show abstract

Bruton's Tyrosine Kinase Deficiency Inhibits Autoimmune Arthritis in Mice but Fails to Block Immune Complex–Mediated Inflammatory Arthritis

Nyhoff

Barron

Johnson

et al. 2016

Arthritis & Rheumatology

View full text Add to dashboard Cite

Objective Bruton’s Tyrosine Kinase (BTK) is a B cell signaling protein that also contributes to innate immunity. BTK-inhibitors prevent autoimmune arthritis, but have off-target effects, and the mechanisms of protection remain unknown. These studies used genetic deletion to investigate the role of BTK in adaptive and innate immune responses that drive inflammatory arthritis. Methods Btk-deficient K/BxN mice were generated to study the role of BTK in a spontaneous model that requires both adaptive and innate immunity. The K/BxN serum transfer model was used to bypass the adaptive system and elucidate the role of BTK in innate immune contributions to arthritis. Results Btk-deficiency conferred disease protection to K/BxN mice, confirming BTK-inhibitor outcomes. B lymphocytes were profoundly reduced, more than in other Btk-deficient models. Subset analysis revealed loss at all developmental stages. Germinal center B cells were also decreased, with downstream effects on T follicular helper numbers, and greatly reduced autoantibodies. In contrast, total IgG was only mildly decreased. Strikingly, and in contrast to small molecule inhibitors, Btk-deficiency had no effect on the serum transfer model of arthritis. Conclusions BTK contributes to autoimmune arthritis primarily via its role in B cell signaling, not innate immune components.

show abstract

B Cell receptor directs the activation of NFAT and NF-κB via distinct molecular mechanisms

Cited by 50 publications

References 67 publications

Transitional B Cell Fate Is Associated with Developmental Stage-Specific Regulation of Diacylglycerol and Calcium Signaling upon B Cell Receptor Engagement

Transitional B Cell Fate Is Associated with Developmental Stage-Specific Regulation of Diacylglycerol and Calcium Signaling upon B Cell Receptor Engagement

A Costimulatory Function for T Cell CD40

Bruton's Tyrosine Kinase Deficiency Inhibits Autoimmune Arthritis in Mice but Fails to Block Immune Complex–Mediated Inflammatory Arthritis

Contact Info

Product

Resources

About