TLR9 Signaling Suppresses the Canonical Plasma Cell Differentiation Program in Follicular B Cells

Area of Science:

• Immunology
• Cell Biology
• Molecular Biology

Background:

• B cell responses to Toll-like receptors (TLRs) vary by B cell subset and TLR member.
• Follicular (FO) B cells proliferate and differentiate into plasmablasts and plasma cells (PBs/PCs) upon TLR4 stimulation, but with delayed kinetics compared to marginal zone B cells.

Purpose of the Study:

• To investigate the effect of TLR9 signaling on FO B cell differentiation into PBs/PCs.
• To compare the roles of TLR4 and TLR9 in controlling plasma cell differentiation programs.

Main Methods:

• Quantitative cell culture conditions optimized for B cell growth and differentiation.
• Analysis of B cell proliferation, PB/PC generation, Ig secretion, cell surface marker expression, and transcription factor activity following TLR stimulation.

Main Results:

• TLR9 signaling via CpG induced vigorous FO B cell proliferation but completely failed to induce PB/PC differentiation.
• TLR9 stimulation resulted in minimal Ig secretion and lacked expression of key PB/PC differentiation markers and transcription factors.
• TLR9 signaling strongly inhibited LPS/TLR4-induced PB/PC differentiation of FO B cells.

Conclusions:

• TLR4 and TLR9 exhibit opposing roles in controlling plasma cell differentiation.
• TLR9 does not induce, and actively inhibits, FO B cell differentiation into plasma cells, contradicting previous findings from high-density cultures.
• These findings have implications for understanding TLR9's role in self-tolerance and humoral immune regulation.