title: Diacylglycerol kinase ζ limits B cell antigen receptor-dependent activation of ERK signaling to inhibit early antibody responses.
abstract: 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 DGKζ, 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 DGKζ 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 DGKζ 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.
authors.affiliation: 1Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Wheeler
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Dong
authors.forename: Robert
authors.initials: R
authors.lastname: Brink
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Zhong
authors.forename: Anthony L
authors.initials: AL
authors.lastname: DeFranco
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000917:Antibody Formation / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D015153:Blotting, Western; D049109:Cell Proliferation; D019852:Diacylglycerol Kinase / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D004075:Diglycerides / Q000276:immunology / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D007075:Immunoglobulin M / Q000097:blood / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D020935:MAP Kinase Signaling System / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009113:Muramidase / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D010950:Plasma Cells / Q000276:immunology / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D051020:bcl-X Protein / Q000276:immunology / Q000378:metabolism
chemical_list: C011439:1,2-diacylglycerol; C494812:Bcl2l1 protein, mouse; D004075:Diglycerides; D007075:Immunoglobulin M; D011947:Receptors, Antigen, B-Cell; D051020:bcl-X Protein; D019852:Diacylglycerol Kinase; C512480:diacylglycerol kinase zeta, mouse; D048049:Extracellular Signal-Regulated MAP Kinases; C421864:hen egg lysozyme; D009113:Muramidase