Notch2 signaling establishes a TLR response program in B cells 3708

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Abstract Description The efficiency with which B cells respond to activation signals varies by subset. Whereas marginal zone (MZ) B cells exhibit rapid activation following stimulation, follicular (FO) B cells adopt delayed effector programs. MZ B cells uniquely exhibit readiness for the plasma cell (PC) fate, differentiating in mere hours independent of mitosis or T cell help. These hallmarks are attributed to their TLR sensitivity; MZ B cells are hyperresponsive to bacterial signals and uniquely among B cells express TLR3, enabling a responsiveness to dsRNA. MZ B cells uniquely require constitutive signaling through the transmembrane receptor Notch2, but whether this signal underlies the functional poising of these cells is unclear. To examine the consequences of Notch2 on B cells with no Notch requirement, we co-cultured stimulated FO B cells on OP9 stromal cells expressing Notch2 ligand delta-like 1 (DL1). DL1 influenced TLR 3 and 4 responses in FO B cells by amplifying the time to first division and the propensity toward PC differentiation and class-switching altogether. Intriguingly, TLR3 responsiveness in B cells appeared to be entirely DL1-driven and dependent on Bruton’s Tyrosine Kinase. Employing a published mathematical model for dividing lymphocytes, we found Notch2 significantly augmented the division rate 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. Funding Sources Supported by NIH F31AI179166-01A1, R21AI174069-02, and T32-AI007632 Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)

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