Integration of signals from the B-cell antigen receptor and the IL-4 receptor leads to a cooperative shift in the cellular response axis

Abstract

Although intracellular signaling events activated through individual cell surface receptors have been characterized in detail, cells are often exposed to multiple stimuli simultaneously in physiological situations. The response elicited then is defined through the cooperative interactions between signals activated by these multiple stimuli. Examples of such instances include cooperativity between individual isoforms of G-protein-coupled receptors, between different growth factor receptors, or between growth factor and integrin receptors. Mechanisms by which the integration of signals emanating from independent receptors influences cellular responses, however, are unknown. In this report, we studied interactions between the antigen and the IL-4 receptors in immature B cells. While stimulation through the B-cell antigen receptor alone causes cell cycle arrest and subsequent apoptosis, the inclusion of IL-4 during stimulation provides a protective effect. We therefore sought to obtain a systems view on how crosstalk between the two respective cell surface receptors modulates the cellular response. We found that, in comparison to the effects of B-cell receptor activation alone, combined stimulation through both receptors enforced a marked reorientation in the ‘survival vs.apoptosis’ axis of the signaling machinery. The consequent modulation of transcription factor activities yielded an integrated network, spanning the signaling and the transcriptional regulatory components, that was now biased towards the recruitment of molecules with a pro-survival function. This alteration in network properties influenced early-induced gene expression, in a manner that could rationalize the antagonistic effect of the IL-4 receptor on B-cell receptor signaling. Importantly, this antagonism was achieved through an expansion in the repertoire of the genes expressed, wherein the newly generated products counteracted the effects of the B-cell receptor-specific subset. Thus the plasticity of the regulatory networks is also experienced at the level of gene expression, and is the resultant pattern obtained that then modulates cell-fate decisions.