Please use this identifier to cite or link to this item: http://hdl.handle.net/123456789/881
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dc.contributor.authorBal, Vineeta-
dc.contributor.authorBasu, Srijani-
dc.contributor.authorKaw, Sheetal-
dc.contributor.authorD'Souza, Lucas-
dc.contributor.authorVaidya, Tushar-
dc.contributor.authorRath, Satyajit-
dc.contributor.authorGeorge, Anna-
dc.date.accessioned2017-03-16T05:34:23Z-
dc.date.available2017-03-16T05:34:23Z-
dc.date.issued2016-08-
dc.identifier.urihttp://hdl.handle.net/123456789/881-
dc.description.abstractCD40 signaling during B cell activation is known to inhibit terminal differentiation and promote memory generation. Blimp-1 is essential for efficient plasma cell (PC) generation, and although CD40 signaling is known to inhibit Blimp-1 induction during B cell activation, the mechanisms involved have been unclear. We report that CD40 signaling induces miR-125b that targets Blimp-1 transcripts, and increases amounts of the ubiquitin ligase Hrd1 that targets BLIMP-1 protein for proteasomal degradation. CD40 signaling also inhibits the early unfolded protein response (UPR) of activated B cells that precedes the induction of terminal differentiation, and Hrd1 feeds into this pathway by targeting the core UPR component IRE-1α. Strikingly, CD40 signaling in the absence of BCR- or TLR-ligation also repressed Blimp-1 transcripts, suggesting that noncognate ligation of CD40 via T-B interactions may repress Blimp-1 in vivo. In support of this, we find that naive B cells purified from CD40-CD154 interaction-deficient mice express higher amounts of Blimp-1 and lower amounts of microRNAs and Hrd1. Higher basal amounts of Blimp-1 in naive CD40(-/-) B cells correlate with an increased tendency of the cells to undergo terminal differentiation upon LPS stimulation. Conversely, a 24-h exposure to CD40 ligation during LPS stimulation of wild-type B cells is sufficient to inhibit PC generation. The data show that CD40-mediated inhibition of PC generation is via engagement of multiple pathways that involve repression of Blimp-1 and inhibition of the UPR that prepares cells to become professional secretors. They also show that constitutive CD40 signaling in vivo involving bystander T-B interactions can calibrate B cell differentiation outcomes.en_US
dc.publisherThe American Association of Immunologists, Incen_US
dc.titleConstitutive CD40 signaling calibrates differentiation outcomes in responding B cells via multiple molecular pathwaysen_US
dc.journalJournal of Immunologyen_US
dc.volumeno197en_US
dc.issueno3en_US
dc.pages761-770en_US
Appears in Collections:Immumo Biology- I, Publications

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