Notch2 signaling instructs TLR-responsive programs in B cells

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Abstract The efficiency with which B cells respond to activation signals varies depending on the subset. Whereas marginal zone (MZ) B cells exhibit rapid activation kinetics following stimulation, follicular (FO) B cells adopt delayed effector programs. Further, MZ B cells uniquely exhibit readiness for the plasma cell (PC) fate, differentiating in mere hours independent of mitosis or T cell help. Some of the many ways MZ B cells achieve poised responsiveness is through sustained Myc levels and mTORC1 activity. MZ B cells uniquely require constitutive signaling through the transmembrane receptor Notch2, but whether this signal underlies the functionally poised nature of these cells is not understood. To examine the consequences of forced Notch2 on B cells with no Notch requirement, we co-cultured stimulated FO B cells on Notch2 ligand-expressing OP9 stromal cells. Notch2 signals modified the response to TLR 3 and 4 stimuli by amplifying the time to first division and the propensity toward PC differentiation altogether. Intriguingly, TLR3 responsiveness in B cells appeared to be entirely Notch2-driven and dependent on the signaling adapter Bruton’s Tyrosine Kinase. Employing a published mathematical model for dividing lymphocytes, we found Notch2 signals significantly augmented the division rate and division destiny of activated B cells. Together, these observations demonstrate a novel role for Notch2 in instructing B cell response programs to TLR signals and their effector outcomes.

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