Suppression of NF-κB and downstream XBP1 by DcR3 contributes to a decrease in antibody secretion

Area of Science:

• Immunology
• Molecular Biology

Background:

• Decoy receptor 3 (DcR3) is a soluble receptor modulating immune cell functions.
• DcR3 is known to suppress B cell proliferation and ameliorate autoimmune diseases.
• The precise role of DcR3 in regulating antibody production remains unclear.

Purpose of the Study:

• To investigate the mechanism by which DcR3 regulates antibody production.
• To determine if DcR3 affects T cell-dependent antibody responses.
• To elucidate the molecular pathways involved in DcR3-mediated regulation of antibody secretion.

Main Methods:

• Utilized a DcR3 transgenic mouse model for in vivo studies.
• Performed in vitro assays using DcR3-Fc fusion protein with B cells.
• Assessed T cell-dependent antibody responses, B cell proliferation, and antibody secretion.
• Analyzed the expression of secretory Igh, Xbp1, and NF-κB activity.
• Investigated the role of X-box binding protein 1 (XBP1) in DcR3-mediated effects.

Main Results:

• DcR3 transgenic mice exhibited impaired T cell-dependent antibody responses.
• DcR3-Fc fusion protein attenuated T cell-dependent antibody production in vitro.
• DcR3-Fc reduced the expression of secretory Igh and Xbp1 in activated B cells.
• DcR3-Fc inhibited NF-κB activity and XBP1 promoter activity, crucial for Xbp1 expression.
• Restoring spliced XBP1 partially rescued the antibody production defect.

Conclusions:

• DcR3 impairs antibody production by suppressing NF-κB activation and subsequent XBP1 expression in B cells.
• This reduction in XBP1 leads to decreased antibody secretion, both in vitro and in vivo.
• DcR3's role extends beyond proliferation suppression to directly impacting antibody production mechanisms.