title: FcγRIIIa-Syk Co-signal Modulates CD4+ T-cell Response and Up-regulates Toll-like Receptor (TLR) Expression.
abstract: CD4(+) T-cells in systemic lupus erythematosus (SLE) patients show altered T-cell receptor signaling, which utilizes Fc-receptor γ-chain FcRγ-Syk. A role for FcγRIIIa activation from immune complex (IC) ligation and sublytic terminal complement complex (C5b-9) in CD4(+) T-cell responses is not investigated. In this study, we show that the ICs present in SLE patients by ligating to FcγRIIIa on CD4(+) T-cells phosphorylate Syk and provide a co-stimulatory signal to CD4(+) T-cells in the absence of CD28 signal. This led to the development of pathogenic IL-17A(+) and IFN-γ(high) CD4(+) T-cells in vitro. Cytokines IL-1β, IL-6, TGF-β1, and IL-23 were the only requirement for the development of both populations. SLE patients CD4(+) T-cells that expressed CD25, CD69, and CD98 bound to ICs showed pSyk and produced IFN-γ and IL-17A. This FcγRIIIa-mediated co-signal differentially up-regulated the expression of IFN pathway genes compared with CD28 co-signal. FcγRIIIa-pSyk up-regulated several toll-like receptor genes as well as the HMGB1 and MyD88 gene transcripts. ICs co-localized with these toll-like receptor pathway proteins. These results suggest a role for the FcγRIIIa-pSyk signal in modulating adaptive immune responses.
authors.affiliation: From the Division of Adult and Pediatric Rheumatology, Saint Louis University School of Medicine, St. Louis, Missouri 63104 chauhana@slu.edu.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Chauhan
authors.affiliation: From the Division of Adult and Pediatric Rheumatology, Saint Louis University School of Medicine, St. Louis, Missouri 63104.
authors.forename: Terry L
authors.initials: TL
authors.lastname: Moore
authors.affiliation: From the Division of Adult and Pediatric Rheumatology, Saint Louis University School of Medicine, St. Louis, Missouri 63104.
authors.forename: Ye
authors.initials: Y
authors.lastname: Bi
authors.affiliation: From the Division of Adult and Pediatric Rheumatology, Saint Louis University School of Medicine, St. Louis, Missouri 63104.
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
mesh_terms: D056704:Adaptive Immunity; D000936:Antigen-Antibody Complex / Q000032:analysis / Q000302:isolation & purification / Q000378:metabolism; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D015938:Complement Membrane Attack Complex / Q000032:analysis / Q000302:isolation & purification / Q000378:metabolism; D024243:HMGB1 Protein / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000097:blood / Q000378:metabolism*; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011505:Protein-Tyrosine Kinases / Q000097:blood / Q000378:metabolism*; D017452:Receptors, IgG / Q000097:blood / Q000378:metabolism*; D017472:Receptors, Interleukin-1 / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D000072377:Syk Kinase; D051193:Toll-Like Receptors / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000936:Antigen-Antibody Complex; D015415:Biomarkers; D015938:Complement Membrane Attack Complex; C496124:FCGR3A protein, human; D024243:HMGB1 Protein; C585491:HMGB1 protein, human; C573415:IFNG protein, human; C508717:IL17A protein, human; D020381:Interleukin-17; D047908:Intracellular Signaling Peptides and Proteins; C507779:MYD88 protein, human; D008562:Membrane Glycoproteins; D053594:Myeloid Differentiation Factor 88; D017452:Receptors, IgG; D017472:Receptors, Interleukin-1; C434984:TIRAP protein, human; D051193:Toll-Like Receptors; D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase
keywords: Fc-γ receptor; T helper cells; autoimmunity; interferon; toll-like receptor (TLR)