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.
Keywords:
Fc-γ receptor; T helper cells; autoimmunity; interferon; toll-like receptor (TLR).
© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adaptive Immunity
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Antigen-Antibody Complex / analysis
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Antigen-Antibody Complex / isolation & purification
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Antigen-Antibody Complex / metabolism
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Biomarkers / blood
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Biomarkers / metabolism
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / metabolism*
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CD4-Positive T-Lymphocytes / pathology
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Cells, Cultured
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Complement Membrane Attack Complex / analysis
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Complement Membrane Attack Complex / isolation & purification
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Complement Membrane Attack Complex / metabolism
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HMGB1 Protein / agonists
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HMGB1 Protein / genetics
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HMGB1 Protein / metabolism
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Humans
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Interferon-gamma / metabolism
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Interleukin-17 / metabolism
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Intracellular Signaling Peptides and Proteins / blood
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Intracellular Signaling Peptides and Proteins / metabolism*
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Lupus Erythematosus, Systemic / blood
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Lupus Erythematosus, Systemic / immunology
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Lupus Erythematosus, Systemic / metabolism*
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Lupus Erythematosus, Systemic / pathology
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Lymphocyte Activation*
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Membrane Glycoproteins / agonists
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / metabolism
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Myeloid Differentiation Factor 88 / agonists
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Myeloid Differentiation Factor 88 / genetics
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Myeloid Differentiation Factor 88 / metabolism
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Phosphorylation
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Protein Processing, Post-Translational
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Protein-Tyrosine Kinases / blood
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Protein-Tyrosine Kinases / metabolism*
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Receptors, IgG / blood
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Receptors, IgG / metabolism*
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Receptors, Interleukin-1 / agonists
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Receptors, Interleukin-1 / genetics
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Receptors, Interleukin-1 / metabolism
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Syk Kinase
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Toll-Like Receptors / agonists*
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Toll-Like Receptors / genetics
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Toll-Like Receptors / metabolism
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Up-Regulation
Substances
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Antigen-Antibody Complex
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Biomarkers
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Complement Membrane Attack Complex
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FCGR3A protein, human
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HMGB1 Protein
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HMGB1 protein, human
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IFNG protein, human
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IL17A protein, human
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Interleukin-17
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Intracellular Signaling Peptides and Proteins
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MYD88 protein, human
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Membrane Glycoproteins
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Myeloid Differentiation Factor 88
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Receptors, IgG
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Receptors, Interleukin-1
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TIRAP protein, human
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Toll-Like Receptors
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Interferon-gamma
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Protein-Tyrosine Kinases
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SYK protein, human
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Syk Kinase