Negative feedback regulation of antigen receptors through calmodulin inhibition of E2A

• Published in: The Journal of immunology (1950) 2012-06, Vol.188 (12), p.6175-6183
• Main Authors: Verma-Gaur, Jiyoti, Hauser, Jannek, Grundström, Thomas
• Format: Article
• Language: English
• Subjects: Animals; B-Lymphocytes - metabolism; Basic Helix-Loop-Helix Transcription Factors - immunology; Basic Helix-Loop-Helix Transcription Factors - metabolism; Blotting, Western; Calmodulin - immunology; Calmodulin - metabolism; Cell Separation; Feedback, Physiological - physiology; Flow Cytometry; Gene Expression Regulation - immunology; Lymphocyte Activation - immunology; Mice; Mice, Knockout; Oligonucleotide Array Sequence Analysis; Real-Time Polymerase Chain Reaction; Receptors, Antigen, B-Cell - immunology; Receptors, Antigen, B-Cell - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction - immunology
• ISSN: 0022-1767; 1550-6606; 1550-6606
• DOI: 10.4049/jimmunol.1103105

Signaling from the BCR is used to judge Ag-binding strengths of the Abs of B cells. BCR signaling enables the selection for successive improvements in the Ag affinity over an extremely broad range of affinities during somatic hypermutation. We show that the mouse BCR is subject to general negative feedback regulation of the receptor proteins, as well as many coreceptors and proteins in signal pathways from the receptor. Thus, the BCR can downregulate itself, which can enable sensitive detection of successive improvements in the Ag affinity over a very large span of affinities. Furthermore, the feedback inhibition of the BCR signalosome and most of its proteins, as well as most other regulations of genes by BCR stimulation, is to a large extent through inhibition of the transcription factor E2A by Ca(2+)/calmodulin.