A model integrating tonic and antigen-triggered BCR signals to predict the survival of primary B cells

Shoya Yasuda,Yang Zhou,Ji-Yang Wang,Yanqing Wang,Masayuki Yamamura

doi:10.1038/s41598-017-13993-x

Shoya Yasuda, Yang Zhou + Show 3 more

Open Access

https://doi.org/10.1038/s41598-017-13993-x

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Journal: Scientific Reports	Publication Date: Nov 2, 2017
Citations: 20	License type: open-access

Affiliation: Tokyo Institute of Technology, Fudan University

Abstract

The BCR constitutively transmits a “tonic” survival signal in the absence of exogenous antigen-binding. However, the strength of tonic BCR signal and its relationship with antigen-triggered survival signal are poorly understood. We found that primary B cells expressing high levels of BCR had elevated BCR tonic signal and increased survival compared with those expressing low levels of BCR. In addition, we found that crosslinking BCR with low doses of F(ab′)2 α-IgM antibodies did not enhance, but rather decreased, B cell survival and that only when most of the BCR were occupied by F(ab′)2 α-IgM antibodies was B cell survival enhanced. Based on these experimental results, we present a mathematical model integrating tonic and antigen-triggered BCR signals. Our model indicates that the signal generated from crosslinked BCR is 4.3 times as strong as the tonic signal generated from free BCR and that the threshold of B cell activation corresponds to the signal generated by crosslinking 61% of the surface BCR. This model also allows the prediction of the survival probability of a B cell based on its initial BCR level and the strength and duration of antigen stimulation, and fits with the mechanism of B cell tolerance.

Highlights

The B cell receptor (BCR) is a heterotrimeric complex consisting of antigen (Ag) binding immunoglobulins and the signal-transducing Igα/Igβ heterodimers
We found that B cell survival in the absence of Ag stimulation positively correlated with BCR levels
In the absence of extrinsic stimuli that induce active gene transcription and protein translation, we think that the amount of the newly synthesized BCR is smaller than the amount degraded, leading to a gradual decrease of surface BCR levels

Summary

Introduction

The B cell receptor (BCR) is a heterotrimeric complex consisting of antigen (Ag) binding immunoglobulins and the signal-transducing Igα/Igβ heterodimers. Studies far have revealed many tyrosine kinases and adaptor molecules that participate in BCR signal transduction triggered by BCR stimulation[12] Both negative[13] and positive[14] feedback mechanisms that regulate BCR signaling have been identified. While B cells do not respond to low doses of Ag stimulation, a robust response can be induced when the Ag dose reaches a certain level The existence of such a threshold can be explained in part by a positive feedback mechanism in the regulation of NF-κB activation[14]. This model allows us to predict the survival probability of a primary B cell cultured under various conditions and provides new insights into the mechanisms of B cell tolerance

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Results

Conclusion