scholarly journals Inhibition of B cell activation following in vivo co-engagement of B cell antigen receptor and Fcγ receptor IIb in non-autoimmune-prone and SLE-prone mice

2021 ◽  
Vol 4 ◽  
pp. 100075
Author(s):  
Seung Y. Chu ◽  
Erik Pong ◽  
Christine Bonzon ◽  
Ning Yu ◽  
Chaim O. Jacob ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Activation ◽  
Antigen Receptor ◽  
B Cell Antigen Receptor ◽  
B Cell Activation ◽  
Fcγ Receptor ◽  
Cell Antigen Receptor ◽  
Cell Antigen

Synthetic biology of B cell activation: understanding signal amplification at the B cell antigen receptor using a rebuilding approach

2019 ◽  
Vol 400 (4) ◽  
pp. 555-563 ◽  
Author(s):  
Yogesh Kulathu ◽  
Christa Zuern ◽  
Jianying Yang ◽  
Michael Reth
Keyword(s):  
Synthetic Biology ◽  
B Cell ◽  
Signal Amplification ◽  
Cell Activation ◽  
Antigen Receptor ◽  
B Cell Antigen Receptor ◽  
B Cell Activation ◽  
Cell Antigen Receptor ◽  
Cell Antigen ◽  
Downstream Signaling

Abstract Upon activation of the B cell antigen receptor (BCR), the spleen tyrosine kinase (Syk) and the Src family kinase Lyn phosphorylate tyrosines of the immunoreceptor tyrosine-based activation motif (ITAM) of Igα and Igβ which further serve as binding sites for the SH2 domains of these kinases. Using a synthetic biology approach, we dissect the roles of different ITAM residues of Igα in Syk activation. We found that a leucine to glycine mutation at the Y+3 position after the first ITAM tyrosine prevents Syk binding and activation. However, a pre-activated Syk can still phosphorylate this tyrosine in trans. Our data show that the formation of a Syk/ITAM initiation complex and trans-ITAM phosphorylation is crucial for BCR signal amplification. In contrast, the interaction of Lyn with the first ITAM tyrosine is not altered by the leucine to glycine mutation. In addition, our study suggests that an ITAM-bound Syk phosphorylates the non-ITAM tyrosine Y204 of Igα only in cis. Collectively, our reconstitution experiments suggest a model whereby first trans-phosphorylation amplifies the BCR signal and subsequently cis-phosphorylation couples the receptor to downstream signaling elements.

scholarly journals TLR4 signals in B lymphocytes are transduced via the B cell antigen receptor and SYK

2017 ◽  
Vol 214 (5) ◽  
pp. 1269-1280 ◽  
Author(s):  
Edina Schweighoffer ◽  
Josquin Nys ◽  
Lesley Vanes ◽  
Nicholas Smithers ◽  
Victor L.J. Tybulewicz
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
Antigen Receptor ◽  
B Cell Antigen Receptor ◽  
B Cell Activation ◽  
Cell Antigen Receptor ◽  
Cell Antigen ◽  
B Cell Survival ◽  
Microbial Products

Toll-like receptors (TLRs) play an important role in immune responses to pathogens by transducing signals in innate immune cells in response to microbial products. TLRs are also expressed on B cells, and TLR signaling in B cells contributes to antibody-mediated immunity and autoimmunity. The SYK tyrosine kinase is essential for signaling from the B cell antigen receptor (BCR), and thus for antibody responses. Surprisingly, we find that it is also required for B cell survival, proliferation, and cytokine secretion in response to signaling through several TLRs. We show that treatment of B cells with lipopolysaccharide, the ligand for TLR4, results in SYK activation and that this is dependent on the BCR. Furthermore, we show that B cells lacking the BCR are also defective in TLR-induced B cell activation. Our results demonstrate that TLR4 signals through two distinct pathways, one via the BCR leading to activation of SYK, ERK, and AKT and the other through MYD88 leading to activation of NF-κB.

scholarly journals Kidins220/ARMS binds to the B cell antigen receptor and regulates B cell development and activation

2015 ◽  
Vol 212 (10) ◽  
pp. 1693-1708 ◽  
Author(s):  
Gina J. Fiala ◽  
Iga Janowska ◽  
Fabiola Prutek ◽  
Elias Hobeika ◽  
Annyesha Satapathy ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Activation ◽  
Antigen Receptor ◽  
Cell Development ◽  
B Cell Development ◽  
B Cell Antigen Receptor ◽  
Independent Manner ◽  
Cell Antigen Receptor ◽  
Cell Antigen ◽  
Bcr Signaling

B cell antigen receptor (BCR) signaling is critical for B cell development and activation. Using mass spectrometry, we identified a protein kinase D–interacting substrate of 220 kD (Kidins220)/ankyrin repeat–rich membrane-spanning protein (ARMS) as a novel interaction partner of resting and stimulated BCR. Upon BCR stimulation, the interaction increases in a Src kinase–independent manner. By knocking down Kidins220 in a B cell line and generating a conditional B cell–specific Kidins220 knockout (B-KO) mouse strain, we show that Kidins220 couples the BCR to PLCγ2, Ca2+, and extracellular signal-regulated kinase (Erk) signaling. Consequently, BCR-mediated B cell activation was reduced in vitro and in vivo upon Kidins220 deletion. Furthermore, B cell development was impaired at stages where pre-BCR or BCR signaling is required. Most strikingly, λ light chain–positive B cells were reduced sixfold in the B-KO mice, genetically placing Kidins220 in the PLCγ2 pathway. Thus, our data indicate that Kidins220 positively regulates pre-BCR and BCR functioning.

scholarly journals Acute Csk inhibition hinders B cell activation by constraining the PI3 kinase pathway

2021 ◽  
Vol 118 (43) ◽  
pp. e2108957118
Author(s):  
Wen Lu ◽  
Katarzyna M. Skrzypczynska ◽  
Arthur Weiss
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
Antigen Receptor ◽  
Negative Regulator ◽  
B Cell Activation ◽  
Cell Antigen Receptor ◽  
Cell Antigen ◽  
Bcr Signaling

T cell antigen receptor (TCR) and B cell antigen receptor (BCR) signaling are initiated and tightly regulated by Src-family kinases (SFKs). SFKs positively regulate TCR signaling in naïve T cells but have both positive and negative regulatory roles in BCR signaling in naïve B cells. The proper regulation of their activities depends on the opposing actions of receptor tyrosine phosphatases CD45 and CD148 and the cytoplasmic tyrosine kinase C-terminal Src kinase Csk. Csk is a major negative regulator of SFKs. Using a PP1-analog-sensitive Csk (CskAS) system, we have previously shown that inhibition of CskAS increases SFK activity, leading to augmentation of responses to weak TCR stimuli in T cells. However, the effects of Csk inhibition in B cells were not known. In this study, we surprisingly found that inhibition of CskAS led to marked inhibition of BCR-stimulated cytoplasmic free calcium increase and Erk activation despite increased SFK activation in B cells, contrasting the effects observed in T cells. Further investigation revealed that acute CskAS inhibition suppressed BCR-mediated phosphatidylinositol 3,4,5-trisphosphate (PIP3) production in B cells. Restoring PIP3 levels in B cells by CD19 cross-linking or SHIP1 deficiency eliminated the negative regulatory effect of CskAS inhibition. This reveals the critical role of Csk in maintaining an appropriate level of SFK activity and regulating PIP3 amounts as a means of compensating for SFK fluctuations to prevent inappropriate B cell activation. This regulatory mechanism controlling PIP3 amounts may also contribute to B cell anergy and self-tolerance.

scholarly journals Inhibition of Fcγ Receptor-Mediated Phagocytosis by a Nonphagocytic Fcγ Receptor

Blood ◽  
1998 ◽  
Vol 91 (5) ◽  
pp. 1762-1768 ◽  
Author(s):  
Sharon Hunter ◽  
Zena K. Indik ◽  
Moo-Kyung Kim ◽  
M. Danielle Cauley ◽  
Jong-Gu Park ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Activation ◽  
Cytoplasmic Domain ◽  
Inhibitory Effect ◽  
B Cell Antigen Receptor ◽  
B Cell Activation ◽  
Fcγ Receptor ◽  
Γ Subunit ◽  
Molecular Events

There are three major classes of human Fcγ receptors (FcγRI, FcγRII, and FcγRIII) and various isoforms of each class are capable of mediating phagocytosis. FcγRIIA is an unusual Fcγ receptor in that it transmits a phagocytic signal in the absence of an additional receptor subunit. The cytoplasmic domain of FcγRIIA contains a conserved motif containing two copies of the sequence YXXL. The tyrosines (Y) within the motif are phosphorylated after receptor crosslinking and the integrity of these conserved sequences is required for efficient phagocytosis. The FcγRIIB receptors, FcγRIIB1 and FcγRIIB2, contain one copy of the cytoplasmic YXXL sequence and do not transmit a phagocytic signal. In B cells, FcγRIIB negatively regulates B-cell activation by the B-cell antigen receptor. Human macrophages express both FcγRIIA and FcγRIIB and while FcγRIIA mediates phagocytosis, the function of FcγRIIB in these cells is unknown. Using the epithelial/fibroblast-like cell line COS-1 as a model to examine the molecular events that regulate the phagocytosis of IgG-coated cells (EA), we investigated the effect of FcγRIIB on FcγRIIA signaling. FcγRIIB inhibited phagocytosis mediated both by FcγRIIA and by a chimeric FcγRIIA receptor containing the extracellular domain of FcγRI and the transmembrane and cytoplasmic domains of FcγRIIA. This inhibition occurred at an early signaling stage because tyrosine phosphorylation of the FcγRIIA cytoplasmic domain was inhibited after concurrent stimulation of these receptors with EA. FcγRIIB mutations showed the importance of the FcγRIIB YXXL for inhibition of FcγRIIA-mediated phagocytosis. Deletion of the FcγRIIB YXXL or conservative replacement of the YXXL tyrosine substantially reduced the inhibitory signal. FcγRIIB had a lesser inhibitory effect on phagocytosis by the Fcγ receptor FcγRIIIA, which requires a γ subunit to mediate a phagocytic signal. These results show that FcγRIIB negatively regulates phagocytic signaling by FcγRIIA and suggests that FcγRIIB plays a role in modulating FcγRIIA function in vivo.

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