No evidence that soluble TACI induces signalling via membrane-expressed BAFF and APRIL in myeloid cells

Area of Science:

• Immunology
• Cell Biology
• Molecular Signaling

Background:

• Tumor Necrosis Factor (TNF) family ligands BAFF/BLyS and APRIL are expressed by myeloid cells and interact with B cell receptors BAFFR, TACI, and BCMA.
• Receptor-ligand engagement can trigger reverse signaling within ligand-expressing cells, a mechanism not fully understood for BAFF and APRIL.

Purpose of the Study:

• To investigate the potential of TACI-Fc (atacicept) to activate reverse signaling through BAFF and APRIL in myeloid cells.
• To understand how TACI-Fc might mediate immune stimulation rather than suppression.

Main Methods:

• Stimulation of bone marrow-derived mouse macrophages with BAFFR-Fc, TACI-Fc, and Fn14-Fc.
• Utilized BAFF- and APRIL-deficient cells to assess ligand dependency.
• Investigated the role of Fc receptor gamma chain and Fc receptor binding-defective TACI-Fc.

Main Results:

• BaffR-Fc and TACI-Fc, but not Fn14-Fc, activated ERK and other signaling pathways in macrophages.
• These activation effects were independent of BAFF or APRIL, as similar profiles were observed in deficient cells.
• Activation correlated with high molecular mass forms of BAFFR-Fc and TACI-Fc and was impaired in Fc receptor gamma chain-deficient macrophages; Fc receptor binding-defective TACI-Fc showed no signal.

Conclusions:

• The study provides no evidence for BAFF or APRIL reverse signaling in myeloid cells under the tested conditions.
• Myeloid cell activation by BAFFR-Fc and TACI-Fc appears to be mediated by Fc receptor interactions, not by ligand-dependent reverse signaling.
• Highlights the importance of specificity controls, particularly Fc receptor interactions, when studying Fc-fusion proteins in myeloid cells.