title: Slc15a4 function is required for intact class switch recombination to IgG2c in response to TLR9 stimulation.
abstract: Signalling through Toll-like receptors (TLRs) by endogenous components of viruses or bacteria can promote antibody (Ab) isotype switching to IgG2a/c. Multiple cell types are capable of responding to TLR stimulation in vivo and the processes underlying TLR-induced Ab isotype switching are not fully defined. Here, we used feeble mice, which are deficient in the peptide/histidine transporter solute carrier family 15 member 4 (Slc15a4), and fail to produce cytokines including interferon alpha (IFNα) in response to TLR9 stimulation, to study Ab isotype switching to IgG2c in response to vaccination. We demonstrate that the production of IgG2c in response to CpGA-adjuvanted vaccines was severely reduced in feeble mice, while a more subtle defect was observed for CpGB. The reduced IgG2c production in feeble could not be ascribed to defective plasmacytoid dendritic cell (pDC) responses alone as we found that splenic cDCs and B cells from feeble mice were also defective in response to TLR9 ligation ex vivo. We conclude that Slc15a4 is required for intact function of TLR9-expressing cells and for effective Ab isotype switching to IgG2c in response to CpG-adjuvanted vaccines.
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Pia
authors.initials: P
authors.lastname: Dosenovic
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Monika
authors.initials: M
authors.lastname: Ádori
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: William C
authors.initials: WC
authors.lastname: Adams
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Gabriel K
authors.initials: GK
authors.lastname: Pedersen
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Martina
authors.initials: M
authors.lastname: Soldemo
authors.affiliation: Department of Genetics, Center for Genetics of Host Defense, UT Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Beutler
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Gunilla B
authors.initials: GB
authors.lastname: Karlsson Hedestam
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D000939:Epitopes / Q000276:immunology; D007114:Immunization; D017578:Immunoglobulin Class Switching / Q000187:drug effects; D016131:Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology; D026901:Membrane Transport Proteins / Q000378:metabolism*; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D017452:Receptors, IgG / Q000378:metabolism*; D011995:Recombination, Genetic / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000378:metabolism*
chemical_list: D000276:Adjuvants, Immunologic; C408982:CPG-oligonucleotide; D000939:Epitopes; C406563:IgG2c receptor; D026901:Membrane Transport Proteins; D009838:Oligodeoxyribonucleotides; D017452:Receptors, IgG; C554281:Slc15a4 protein, mouse; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9