title: TACI deficiency leads to alternatively activated macrophage phenotype and susceptibility to Leishmania infection.
abstract: The TNF family member, transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI), is a key molecule for plasma cell maintenance and is required in infections where protection depends on antibody response. Here, we report that compared with WT mouse, TACI KO Μϕs expressed lower levels of Toll-like receptors (TLRs), CD14, myeloid differentiation primary response protein 88, and adaptor protein Toll/IL-1 receptor domain-containing adapter-inducing IFN-β and responded poorly to TLR agonists. Analysis of Μϕ phenotype revealed that, in the absence of TACI, Μϕs adapt the alternatively activated (M2) phenotype. Steady-state expression levels for M2 markers IL-4Rα, CD206, CCL22, IL-10, Arg1, IL1RN, and FIZZ1 were significantly higher in TACI KO Μϕ than in WT cells. Confirming their M2 phenotype, TACI-KO Mϕs were unable to control Leishmania major infection in vitro, and intradermal inoculation of Leishmania resulted in a more severe manifestation of disease than in the resistant C57BL/6 strain. Transfer of WT Μϕs to TACI KO mice was sufficient to significantly reduce disease severity. TACI is likely to influence Mϕ phenotype by mediating B cell-activating factor belonging to the TNF family (BAFF) and a proliferation inducing ligand (APRIL) signals because both these ligands down-regulated M2 markers in WT but not in TACI-deficient Μϕs. Moreover, treatment of Μϕs with BAFF or APRIL enhanced the clearance of Leishmania from cells only when TACI is expressed. These findings may have implications for understanding the shortcomings of host response in newborns where TACI expression is reduced and in combined variable immunodeficiency patients where TACI signaling is ablated.
authors.affiliation: Laboratory of Bacterial Polysaccharides, Division of Bacterial Parasitic and Allergenic Products, US Food and Drug Administration, Silver Spring, MD 20993;
authors.forename: Windy R
authors.initials: WR
authors.lastname: Allman
authors.affiliation: Division of Emerging and Transfusion Transmitted Diseases, US Food and Drug Administration, Silver Spring, MD 20993;
authors.forename: Ranadhir
authors.initials: R
authors.lastname: Dey
authors.affiliation: Laboratory of Bacterial Polysaccharides, Division of Bacterial Parasitic and Allergenic Products, US Food and Drug Administration, Silver Spring, MD 20993;
authors.forename: Lunhua
authors.initials: L
authors.lastname: Liu
authors.affiliation: Laboratory of Bacterial Polysaccharides, Division of Bacterial Parasitic and Allergenic Products, US Food and Drug Administration, Silver Spring, MD 20993;
authors.forename: Shafiuddin
authors.initials: S
authors.lastname: Siddiqui
authors.affiliation: Laboratory of Bacterial Polysaccharides, Division of Bacterial Parasitic and Allergenic Products, US Food and Drug Administration, Silver Spring, MD 20993;
authors.forename: Adam S
authors.initials: AS
authors.lastname: Coleman
authors.affiliation: Division of Emerging and Transfusion Transmitted Diseases, US Food and Drug Administration, Silver Spring, MD 20993;
authors.forename: Parna
authors.initials: P
authors.lastname: Bhattacharya
authors.affiliation: Laboratory of Bacterial Polysaccharides, Division of Bacterial Parasitic and Allergenic Products, US Food and Drug Administration, Silver Spring, MD 20993;
authors.forename: Masahide
authors.initials: M
authors.lastname: Yano
authors.affiliation: Laboratory of Bacterial Polysaccharides, Division of Bacterial Parasitic and Allergenic Products, US Food and Drug Administration, Silver Spring, MD 20993;
authors.forename: Kadriye
authors.initials: K
authors.lastname: Uslu
authors.affiliation: Microscopy and Imaging Core Facility, Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, MD 20993.
authors.forename: Kazuyo
authors.initials: K
authors.lastname: Takeda
authors.affiliation: Division of Emerging and Transfusion Transmitted Diseases, US Food and Drug Administration, Silver Spring, MD 20993;
authors.forename: Hira L
authors.initials: HL
authors.lastname: Nakhasi
authors.affiliation: Laboratory of Bacterial Polysaccharides, Division of Bacterial Parasitic and Allergenic Products, US Food and Drug Administration, Silver Spring, MD 20993; mustafa.akkoyunlu@fda.hhs.gov.
authors.forename: Mustafa
authors.initials: M
authors.lastname: Akkoyunlu
mesh_terms: D000818:Animals; D053264:B-Cell Activating Factor / Q000378:metabolism; D049109:Cell Proliferation; D005786:Gene Expression Regulation; D007891:Leishmania / Q000472:pathogenicity*; D007896:Leishmaniasis / Q000276:immunology* / Q000378:metabolism; D008024:Ligands; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D010766:Phosphorylation; D015398:Signal Transduction; D053303:Transmembrane Activator and CAML Interactor Protein / Q000235:genetics / Q000378:metabolism*; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000378:metabolism
chemical_list: D053264:B-Cell Activating Factor; D008024:Ligands; D018950:Lipopolysaccharide Receptors; C486361:Tnfrsf13b protein, mouse; C505720:Tnfsf13b protein, mouse; D053303:Transmembrane Activator and CAML Interactor Protein; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13
keywords: APRIL; BAFF; Leishmania; TACI; macrophage