Constitutive CD40 Signaling Calibrates Differentiation Outcomes in Responding B Cells via Multiple Molecular Pathways

Abstract

CD40 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.

CBX3 promotes clear cell renal carcinoma through PI3K/AKT activation and aberrant immunity

“…D40, a costimulatory receptor in B cells and one of the TNF receptor family members, is known to in uence the fate of B cells [48] . Previous studies have shown that CD40 signaling can stimulate B cell expansion and differentiation and its strength can regulate the development of various memory B cell subtypes [49][50][51] . Furthermore, aberrations in these driver genes have been widely demonstrated to cause hyperactivation of the PI3K signaling pathway.…”

The impact of clopidogrel on plasma-soluble CD40 ligand levels in systemic lupus erythematosus patients: the CLOPUS phase I/II pilot study

“…isotypique des centrocytes, diversifiant les fragments Fc des immunoglobulines et permettant l'expression des isotypes IgG, IgA et IgE. La différentiation terminale des centrocytes en cellules B mémoires ou en plasmablastes est également sous la dépendance de la signalisation du CD40, l'activation de cette voie orientant préférentiellement vers la cellule B mémoire et inhibant la génération de plasmocytes(126,127).Les lymphocytes B ont une capacité à initier le « priming » du lymphocyte T en agissant comme des CPA. Après leur prise en charge de l'antigène, les lymphocytes B ont un phénotype activé et une augmentation des molécules B7 et du CMH de classe II.…”