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Sci. Signal., 15 October 2013
Vol. 6, Issue 297, p. ra91
Diacylglycerol Kinase Limits B Cell Antigen Receptor–Dependent Activation of ERK Signaling to Inhibit Early Antibody Responses
Matthew L. Wheeler1,2*,
Matthew B. Dong1,
Xiao-Ping Zhong4, and
Anthony L. DeFranco1
1 Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA. 2 Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA. 3 Immunology Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia. 4 Departments of Pediatrics and Immunology, Duke University Medical Center, Durham, NC 27710, USA.
* Present address: Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Signaling downstream of the B cell antigen receptor (BCR) is tightly regulated to enable cells to gauge the strength and duration of antigen-receptor interactions and to respond appropriately. We investigated whether metabolism of the second messenger diacylglycerol (DAG) by members of the family of DAG kinases (DGKs) played a role in modulating the magnitude of signaling by DAG downstream of the BCR. In the absence of DGK, the threshold for BCR signaling, measured as activation of the Ras–extracellular signal–regulated kinase (ERK) pathway, was markedly reduced in mature follicular B cells, which resulted in enhanced responses to antigen in vitro and in vivo. Inhibition of DAG signaling by DGK limited the number of antibody-secreting cells that were generated early in response to T cell–independent type 2 antigens, as well as to T cell–dependent antigens. Furthermore, the effect of loss of DGK closely resembled the effect of increasing the affinity of the BCR for antigen during the T cell–dependent antibody response. These results suggest that the magnitude of DAG signaling is important for translating the affinity of the BCR for antigen into the amount of antibody produced during the early stages of an immune response.
Citation: M. L. Wheeler, M. B. Dong, R. Brink, X.-P. Zhong, A. L. DeFranco, Diacylglycerol Kinase Limits B Cell Antigen Receptor–Dependent Activation of ERK Signaling to Inhibit Early Antibody Responses. Sci. Signal.6, ra91 (2013).
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[DOI: 10.1126/scisignal.2003113] |Editor's Summary »|Abstract »|Full Text »|PDF »|Supplementary Materials »
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[DOI: 10.1126/scisignal.2002820] |Editor's Summary »|Abstract »|Full Text »|PDF »|Supplementary Materials »