Slc15a4 function is required for intact class switch recombination to IgG2c in response to TLR9 stimulation

Area of Science:

• Immunology
• Molecular Biology
• Vaccinology

Background:

• Antibody (Ab) isotype switching to IgG2a/c is promoted by Toll-like receptor (TLR) signaling.
• The precise cellular mechanisms of TLR-induced Ab isotype switching remain incompletely understood.

Purpose of the Study:

• To investigate the role of solute carrier family 15 member 4 (Slc15a4) in TLR9-mediated antibody IgG2c isotype switching.
• To determine the impact of Slc15a4 deficiency on immune responses to CpG-adjuvanted vaccines.

Main Methods:

• Utilized feeble mice, genetically deficient in Slc15a4, which exhibit impaired cytokine production upon TLR9 stimulation.
• Administered CpG-adjuvanted vaccines to feeble and wild-type mice to assess IgG2c production.
• Performed ex vivo analysis of splenic dendritic cells (DCs) and B cells from feeble mice following TLR9 ligation.

Main Results:

• Feeble mice exhibited significantly reduced IgG2c production in response to CpGA-adjuvanted vaccines, with a less pronounced defect for CpGB.
• The defect in IgG2c production was not solely due to impaired plasmacytoid dendritic cell (pDC) function.
• Splenic conventional DCs (cDCs) and B cells from feeble mice also showed defective responses to TLR9 stimulation ex vivo.

Conclusions:

• Slc15a4 is essential for the proper function of TLR9-expressing cells, including pDCs, cDCs, and B cells.
• Slc15a4 plays a critical role in effective antibody IgG2c isotype switching in response to CpG-adjuvanted vaccines.