Signal Transduction by the B‐Cell Antigen Receptor

DeFranco, Anthony L.; Richards, Jennifer C.; Blum, John D.; Stevens, Tracy L.; Law, Debbie A.; Chan, Vivien W.; Datta, Sandip K.; Foy, Shaun P.; Hourihane, Sharon L.; Gold, Michael R.; Matsuuchi, Linda

doi:10.1111/j.1749-6632.1995.tb26662.x

Cited by 35 publications

(23 citation statements)

References 26 publications

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“…Similar results have been reported with other T-cell accessory molecules, such as CD3 and CD5 [28], and for FcR on a variety of immune cells [29], and Iga and b on B cells [30]. Here we found that WC1 was co-immunoprecipitated with anti-src or anti-lyn antibodies, demonstrating an association between WC1 and src family kinase members in ex vivo cells.…”

Section: Wc1 Cytoplasmic Tail Serines Are Phosphorylated Independentlsupporting

confidence: 90%

Tyrosine phosphorylation of scavenger receptor cysteine‐rich WC1 is required for the WC1‐mediated potentiation of TCR‐induced T‐cell proliferation

et al. 2009

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Workshop cluster 1 (WC1) molecules are transmembrane glycoproteins uniquely expressed by cd T cells. They belong to the scavenger receptor cysteine-rich superfamily and are encoded by a multi-gene family, which is divided on the basis of antibody reactivity, into three groups, WC1.1, WC1.2, and WC1.3. The potential role of WC1 as a co-stimulatory molecule for the cd TCR is suggested by the presence of several tyrosinebased motifs in their intracellular domains. In this study, we found that WC1 was constitutively phosphorylated in ex vivo bovine cd T cells and associated with src family tyrosine kinases. Crosslinking of WC1 molecules resulted in an increase in WC1 phosphorylation and co-crosslinking of WC1 and cd TCR together prolonged WC1 phosphorylation. We identified the second tyrosine residue as the primary phosphorylation target in WC1.1 and WC1.2 intracellular sequences in both in vitro and in vivo assays. The cytoplasmic tails of WC1.1 and WC1.2 were phosphorylated on serine and PKC activity was required for PMA-induced endocytosis of WC1.1 or WC1.2. We found that phosphorylation of the second tyrosine in the WC1 cytoplasmic domain was required for the WC1-mediated potentiation of TCR-induced T-cell proliferation, suggesting that WC1 acts as a co-stimulatory molecule for cd TCR.Key words: Bovine . Cell surface molecules . gd T cells . Signal transduction IntroductionIn adult chickens, ruminants and pigs, unlike in mice and humans, gd T cells can constitute 30% of total PBMC [1]. A majority of these gd T cells in ruminants bear the glycoprotein lineage marker Workshop cluster 1 (WC1) on their surface. Based on the profiles of their gene expression, WC1 1 gd T cells of cattle represent the inflammatory population, whereas WC1 À gd T cells are regulatory cells [2,3]. WC1, a member of the scavenger receptor cysteine-rich (SRCR) superfamily, is categorized into group B along with CD5, CD6, and CD163, based on the organization of cysteine residues in its extracellular SRCR domains [4]. Like the SRCR family member SpSRCR, which is expressed in the immune cells of the purple sea urchin [5], WC1 molecules are products of a large gene family, and thus have the potential to increase the diversity of immune responses independently of the adaptive immune response receptor, i.e. the TCR.Bovine gd T cells express at least three known variants, WC1.1, WC1.2, and WC1.3, which are defined by antibodies recognizing unknown epitopes on their SRCR domains [6]. WC1.1 and WC1.2 are expressed on two mostly non-overlapping subsets of bovine gd T cells, and WC1.3 is expressed on a small 254subpopulation of WC1.1 1 cells. Cytokine production and cellular proliferation in response to stimulation vary according to the forms of WC1 expressed by gd T cells [7]. Ex vivo WC1.1 1 gd T cells, but not WC1.2 1 gd T cells, proliferate well to the gd T-cell antigens of Leptospira, and produce IFN-g in response to either antigen or 8].The correlation of the expression of a variable WC1 gene product with a cellular immune response to antigen su...

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Section: Wc1 Cytoplasmic Tail Serines Are Phosphorylated Independentlsupporting

confidence: 90%

Tyrosine phosphorylation of scavenger receptor cysteine‐rich WC1 is required for the WC1‐mediated potentiation of TCR‐induced T‐cell proliferation

et al. 2009

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“…BCR activation recruits members of nonreceptor protein tyrosine kinases (PTKs) of the Src, Syk, Tec, and Csk families (3)(4)(5)(6). BCR evoked tyrosine phosphorylation of Lyn, and Syk triggers a biochemical cascade in which a variety of cellular proteins become tyrosine phosphorylated (3,7).…”

Section: S Timulation Of the B Cell Receptor (Bcr)mentioning

confidence: 99%

Microarray Analysis of Lyn-Deficient B Cells Reveals Germinal Center-Associated Nuclear Protein and Other Genes Associated with the Lymphoid Germinal Center

Korade

Caudell

Gao

et al. 2004

The Journal of Immunology

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Lyn is the only member of the Src family expressed in DT40 B cells, which provide a unique model to study the singular contribution of this protein tyrosine kinase (PTK) family to cell signaling. In these cells, gene ablation of Lyn leads to defective B cell receptor signaling. Complementary DNA array analysis of Lyn-deficient DT40 cells shows that the absence of Lyn leads to down-regulation of numerous genes encoding proteins involved in B cell receptor signaling, proliferation, control of transcription, immunity/inflammation response, and cytoskeletal organization. Most of these expression changes have not been previously associated with Lyn PTK signaling. They include alterations in mRNA levels of germinal center-associated nuclear protein (germinal center-associated DNA primase) (GANP), CD74, CD22, NF-κB, elongation factor 1α, CD79b, octamer binding factor 1, Ig H chain, stathmin, and γ-actin. Changes in GANP expression were also confirmed in Lyn-deficient mice, suggesting that Lyn PTK has a unique function not compensated for by other Src kinases. Because Lyn-deficient mice have impaired development of germinal centers in spleen, the decreased expression of GANP in the Lyn-deficient DT40 cell line and Lyn-deficient mice suggests that Lyn controls the formation and proliferation of germinal centers via GANP. GANP promoter activity was higher in wild-type vs Lyn-deficient cells. Mutation of the PU.1 binding site reduced activity in wild-type cells and had no effect in Lyn-deficient cells. The presence of Lyn enhanced PU.1 expression in a Northern blot. Thus, the following new signaling pathway has been described: Lyn→PU.1→GANP.

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“…6 This promotion implies the recruitment of several transcription factors (TFs) that influence B-cell proliferation, differentiation, cytokine production, and apoptosis. 7,8 The outcome of BCR engagement is variable, depending on the status of the B cell and commitment of coreceptors.…”

Section: Introductionmentioning

confidence: 99%

IVIg modulates BCR signaling through CD22 and promotes apoptosis in mature human B lymphocytes

Séïté

Cornec

Renaudineau

et al. 2010

Blood

133

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IntroductionAlthough intravenous immunoglobulin (IVIg) is widely used to treat idiopathic thrombocytopenic purpura, Kawasaki disease, systemic lupus erythrematosus and Guillain-Barré syndrome, 1 the mechanisms by which immune functions are influenced by such preparations remain to be delineated. 2 Because B lymphocytes play a central role in the immunopathologic processes that cause these diseases, several studies have suggested that B cells are the target cells for the beneficial effect of IVIg. For this hypothesis to apply, IVIg would modulate a broad range of B lymphocyte functions including activation, proliferation, 3 and survival. 4 In other words, IVIg would interfere with the expression of genes and, potentially, the functions of proteins involved in cell growth and death.The interaction between IVIg and B lymphocytes could thus modulate intracellular signaling resulting from the engagement of the B-cell antigen (Ag) receptor (BCR). The earliest signaling events of the ensuing cascade involves activation of the Src-family protein-tyrosine kinase (PTK) Lyn. 5 Activated Lyn phosphorylates immunoreceptor tyrosine-based activation motifs (ITAMs) on the cytoplasmic domain of the membrane ␣ and ␤ proteins (CD79␣ and CD79␤). Once phosphorylated, CD79␣ and CD79␤ recruit another PTK protein, Syk. Syk associates with phospho-ITAMs via its tandem Src-homology 2 (SH2) domains, is phosphorylated, and in turn, phosphorylates the adaptor protein B-cell linker protein (BLNK). The adaptor thus acquires the capacity to bind to and activate Bruton's tyrosine kinase (Btk). This sequence of signaling events leads to the activation of phospholipase C␥2 (PLC␥2), hydrolysis of phosphatidylinisitol-4,5-bisphosphate and the production of inositol-1,4,5-trisphosphate.As a result, released intracellular calcium synergizes with other signals to induce gene transcription. 6 This promotion implies the recruitment of several transcription factors (TFs) that influence B-cell proliferation, differentiation, cytokine production, and apoptosis. 7,8 The outcome of BCR engagement is variable, depending on the status of the B cell and commitment of coreceptors. The latter dictate the ultimate response and associate positive regulators (such as CD19 and CD21) and negative regulators (such as CD22 and CD32) and these ultimately determine the outcome of B-cell responses. Under normal conditions, both groups of proteins are expressed at varying levels on the surface of all B lymphocytes and their engagement contributes to setting the threshold of B-cell activation. This is often achieved by increasing or decreasing tyrosine phosphorylation, thereby enhancing or reducing signal transduction. 9 CD22 conveys the SH2 domain-containing phosphatase 1 (SHP-1) over to the BCR through the immunoreceptor tyrosinebased inhibition motifs (ITIMs) located in its cytoplasmic domain. 10 This membrane protein belongs to the sialic acid (SA)-binding Ig-like lectin (Siglec) superfamily, with 7 Ig-like extracellular domains and an amino-terminal Ig domain. CD22 is u...

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Signal Transduction by the B‐Cell Antigen Receptor

Cited by 35 publications

References 26 publications

Tyrosine phosphorylation of scavenger receptor cysteine‐rich WC1 is required for the WC1‐mediated potentiation of TCR‐induced T‐cell proliferation

Tyrosine phosphorylation of scavenger receptor cysteine‐rich WC1 is required for the WC1‐mediated potentiation of TCR‐induced T‐cell proliferation

Microarray Analysis of Lyn-Deficient B Cells Reveals Germinal Center-Associated Nuclear Protein and Other Genes Associated with the Lymphoid Germinal Center

IVIg modulates BCR signaling through CD22 and promotes apoptosis in mature human B lymphocytes

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