CD19 is essential for B cell activation by promoting B cell receptor–antigen microcluster formation in response to membrane-bound ligand

Depoil, David; Fleire, Sebastian J.; Treanor, Bebhinn; Weber, Michele; Harwood, Naomi E.; Marchbank, Kevin J.; Tybulewicz, Victor L. J.; Batista, Facundo D.

doi:10.1038/ni1547

Cited by 317 publications

(375 citation statements)

References 50 publications

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“…4 B and C). In contrast, Syk phosphorylation induced by BCR cross-linking on the B-cell surface was found exclusively at the outer rim of the cell, consistent with cap formation and localized signaling from the plasma membrane (61,62) (Fig. 4 B and C).…”

Section: Syk Controls Tyrosine Phosphorylation Of Major Pathways Invomentioning

confidence: 80%

A respiratory chain controlled signal transduction cascade in the mitochondrial intermembrane space mediates hydrogen peroxide signaling

Patterson

Gerbeth

Thiru

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Reactive oxygen species (ROS) such as hydrogen peroxide (H2O2) govern cellular homeostasis by inducing signaling. H2O2 modulates the activity of phosphatases and many other signaling molecules through oxidation of critical cysteine residues, which led to the notion that initiation of ROS signaling is broad and nonspecific, and thus fundamentally distinct from other signaling pathways. Here, we report that H2O2 signaling bears hallmarks of a regular signal transduction cascade. It is controlled by hierarchical signaling events resulting in a focused response as the results place the mitochondrial respiratory chain upstream of tyrosine-protein kinase Lyn, Lyn upstream of tyrosine-protein kinase SYK (Syk), and Syk upstream of numerous targets involved in signaling, transcription, translation, metabolism, and cell cycle regulation. The active mediators of H2O2 signaling colocalize as H2O2 induces mitochondria-associated Lyn and Syk phosphorylation, and a pool of Lyn and Syk reside in the mitochondrial intermembrane space. Finally, the same intermediaries control the signaling response in tissues and species responsive to H2O2 as the respiratory chain, Lyn, and Syk were similarly required for H2O2 signaling in mouse B cells, fibroblasts, and chicken DT40 B cells. Consistent with a broad role, the Syk pathway is coexpressed across tissues, is of early metazoan origin, and displays evidence of evolutionary constraint in the human. These results suggest that H2O2 signaling is under control of a signal transduction pathway that links the respiratory chain to the mitochondrial intermembrane space-localized, ubiquitous, and ancient Syk pathway in hematopoietic and nonhematopoietic cells.

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Section: Syk Controls Tyrosine Phosphorylation Of Major Pathways Invomentioning

confidence: 80%

A respiratory chain controlled signal transduction cascade in the mitochondrial intermembrane space mediates hydrogen peroxide signaling

Patterson

Gerbeth

Thiru

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…It is unclear why CD19 is required for IDO induction after TLR9 ligation in vivo. CD19 regulates intracellular TLR signaling in B cells, lowers B-cell activation thresholds, and is required for optimal B-cell responses to membrane-bound antigens (25)(26)(27)(28). Thus, CD19 may transduce intracellular signals from TLR9 in IDO-competent cells.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, like DCs-but unlike resting B cells-IDO-competent cells were potent T-cell APCs when not induced to express IDO, confirming that IDOcompetent cells are a distinct cell subtype with attributes of B cells and DCs. CD19 amplifies B cell receptor (BCR) signaling and promotes Bcell responses to membrane-bound antigens (25)(26)(27)(28). We hypothesized that CD19 is required for IDO induction in DCs.…”

Section: B Cells | T-cell Regulation | Cd19mentioning

confidence: 99%

B-lymphoid cells with attributes of dendritic cells regulate T cells via indoleamine 2,3-dioxygenase

Johnson¹,

Kahler²,

Baban³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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A discrete population of splenocytes with attributes of dendritic cells (DCs) and coexpressing the B-cell marker CD19 is uniquely competent to express the T-cell regulatory enzyme indoleamine 2,3-dioxygenase (IDO) in mice treated with TLR9 ligands (CpGs). Here we show that IDO-competent cells express the B-lineage commitment factor Pax5 and surface immunoglobulins. CD19 ablation abrogated IDO-dependent T-cell suppression by DCs, even though cells with phenotypic attributes matching IDO-competent cells developed normally and expressed IDO in response to interferon γ. Consequently, DCs and regulatory T cells (Tregs) did not acquire T-cell regulatory functions after TLR9 ligation, providing an alternative perspective on the known T-cell regulatory defects of CD19-deficient mice. DCs from B-cell-deficient mice expressed IDO and mediated T-cell suppression after TLR9 ligation, indicating that B-cell attributes were not essential for B-lymphoid IDO-competent cells to regulate T cells. Thus, IDO-competent cells constitute a distinctive B-lymphoid cell type with quintessential T-cell regulatory attributes and phenotypic features of both B cells and DCs. B cells | T-cell regulation | CD19I ndoleamine 2,3-dioxygenase (IDO) is an intracellular enzyme expressed in response to interferons (IFNs) at sites of inflammation. IDO inhibitors exacerbated T-cell-mediated pathology in models of tumor growth and autoimmune, infectious, and allergic diseases, and are currently under evaluation as potential tumor vaccine adjuvants in clinical settings (1, 2). By analogy to the tumor-protective effects of IDO, some pathogens may exploit IDO to facilitate persistence and IDO may attenuate vaccine-induced immunity (3-6). Consistent with this paradigm, artificially enhanced IDO activity attenuated graft versus host disease after bone marrow engraftment and prolonged rat lung allograft survival (7-9). Thus, IDO-dependent T-cell regulation occurs in multiple settings of chronic inflammation relevant to clinical syndromes.Despite the potential benefits of manipulating IDO activity to improve therapy in chronic inflammatory syndromes, little is known about the cellular basis of IDO-mediated T-cell regulation in physiologic settings. Antigen presenting cells (APCs) expressing IDO, such as dendritic cells (DCs), activate regulatory T cells (Tregs) and directly suppress effector T cells at sites of tissue inflammation (10, 11). Cells with functional and phenotypic attributes of DCs in mice and humans are competent to express IDO and regulate T-cell responses (11-15). In mice, splenocytes uniquely competent to mediate T-cell suppression via IDO after in vivo treatment with TLR9 ligands (CpGs) were a rare cell type located in splenic red pulp with phenotypic attributes of DCs (CD11c, CD8α, CD80/86, MHCII). IDO-competent cells also expressed B220 and the B-cell lineage marker CD19, but not the plasmacytoid DC (pDC) marker PDCA/120G8 (13). After CTLA4-Ig and CpG treatment, IDO-competent cells produced IFNα (15, 16), a functional attribute of pDCs and ...

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“…Microclusters of BCR were formed rapidly following recognition of antigen and recruited various cellular mediators and adaptors. Interestingly, the co-receptor CD19 was found to be essential for the formation of BCR microclusters and B-cell spreading [13].…”

Section: High Spatial Resolution: Atomic Force and Single Molecule Immentioning

confidence: 99%

Imaging immunity

2009

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CD19 is essential for B cell activation by promoting B cell receptor–antigen microcluster formation in response to membrane-bound ligand

Cited by 317 publications

References 50 publications

A respiratory chain controlled signal transduction cascade in the mitochondrial intermembrane space mediates hydrogen peroxide signaling

A respiratory chain controlled signal transduction cascade in the mitochondrial intermembrane space mediates hydrogen peroxide signaling

B-lymphoid cells with attributes of dendritic cells regulate T cells via indoleamine 2,3-dioxygenase

Imaging immunity

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