Dataset Information

Monophosphorylation of CD79a and CD79b ITAM motifs initiates a SHIP-1 phosphatase-mediated inhibitory signaling cascade required for B cell anergy.

ABSTRACT: Anergic B cells are characterized by impaired signaling and activation after aggregation of their antigen receptors (BCR). The molecular basis of this impairment is not understood. In studies reported here, Src homology-2 (SH2)-containing inositol 5-phosphatase SHIP-1 and its adaptor Dok-1 were found to be constitutively phosphorylated in anergic B cells, and activation of this inhibitory circuit was dependent on Src-family kinase activity and consequent to biased BCR immunoreceptor tyrosine-based activation motif (ITAM) monophosphorylation. B cell-targeted deletion of SHIP-1 caused severe lupus-like disease. Moreover, absence of SHIP-1 in B cells led to loss of anergy as indicated by restoration of BCR signaling, loss of anergic surface phenotype, and production of autoantibodies. Thus, chronic BCR signals maintain anergy in part via ITAM monophosphorylation-directed activation of an inhibitory signaling circuit involving SHIP-1 and Dok-1.

SUBMITTER: O'Neill SK

PROVIDER: S-EPMC3232011 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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Publications

Monophosphorylation of CD79a and CD79b ITAM motifs initiates a SHIP-1 phosphatase-mediated inhibitory signaling cascade required for B cell anergy.

O'Neill Shannon K SK Getahun Andrew A Gauld Stephen B SB Merrell Kevin T KT Tamir Idan I Smith Mia J MJ Dal Porto Joseph M JM Li Quan-Zhen QZ Cambier John C JC

Immunity 20111109 5

Anergic B cells are characterized by impaired signaling and activation after aggregation of their antigen receptors (BCR). The molecular basis of this impairment is not understood. In studies reported here, Src homology-2 (SH2)-containing inositol 5-phosphatase SHIP-1 and its adaptor Dok-1 were found to be constitutively phosphorylated in anergic B cells, and activation of this inhibitory circuit was dependent on Src-family kinase activity and consequent to biased BCR immunoreceptor tyrosine-bas ...[more]

PMID: 22078222

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Project description:Key pointsInhibitory-interneuron networks, consisting of multiple forms of circuit motifs including reciprocal (inhibitory interneurons inhibiting other interneurons) and feedforward (inhibitory interneurons inhibiting principal neurons) connections, are crucial in processing sensory information. The present study applies a statistical method to in vivo multichannel spike trains of dorsal cochlear nucleus neurons to disentangle reciprocal and feedforward-inhibitory motifs. After inducing input-specific plasticity, reciprocal and feedforward inhibition are found to be differentially regulated, and the combined effect synergistically modulates circuit output. The findings highlight the interplay among different circuit motifs as a key element in neural computation.AbstractInhibitory interneurons play an essential role in neural computations by utilizing a combination of reciprocal (interneurons inhibiting each other) and feedforward (interneuron inhibiting the principal neuron) inhibition to process information. To disentangle the interplay between the two inhibitory-circuit motifs and understand their effects on the circuit output, in vivo recordings were made from the guinea pig dorsal cochlear nucleus, a cerebellar-like brainstem circuit. Spikes from inhibitory interneurons (cartwheel cell) and principal output neurons (fusiform cell) were compared before and after manipulating their common multimodal input. Using a statistical model based on the Cox method of modulated renewal process of spike train influence, reciprocal- and feedforward-inhibition motifs were quantified. In response to altered multimodal input, reciprocal inhibition was strengthened while feedforward inhibition was weakened, and the two motifs combined to modulate fusiform cell output and acoustic-driven responses. These findings reveal the cartwheel cell's role in auditory and multimodal processing, as well as illustrated the balance between different inhibitory-circuit motifs as a key element in neural computation.

Dataset Information

Monophosphorylation of CD79a and CD79b ITAM motifs initiates a SHIP-1 phosphatase-mediated inhibitory signaling cascade required for B cell anergy.

Publications

Monophosphorylation of CD79a and CD79b ITAM motifs initiates a SHIP-1 phosphatase-mediated inhibitory signaling cascade required for B cell anergy.

Similar Datasets

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