FcγRIIIa-Syk Co-signal Modulates CD4+ T-cell Response and Up-regulates Toll-like Receptor (TLR) Expression

J Biol Chem. 2016 Jan 15;291(3):1368-86. doi: 10.1074/jbc.M115.684795. Epub 2015 Nov 18.

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).

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptive Immunity
  • Antigen-Antibody Complex / analysis
  • Antigen-Antibody Complex / isolation & purification
  • Antigen-Antibody Complex / metabolism
  • Biomarkers / blood
  • Biomarkers / metabolism
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism*
  • CD4-Positive T-Lymphocytes / pathology
  • Cells, Cultured
  • Complement Membrane Attack Complex / analysis
  • Complement Membrane Attack Complex / isolation & purification
  • Complement Membrane Attack Complex / metabolism
  • HMGB1 Protein / agonists
  • HMGB1 Protein / genetics
  • HMGB1 Protein / metabolism
  • Humans
  • Interferon-gamma / metabolism
  • Interleukin-17 / metabolism
  • Intracellular Signaling Peptides and Proteins / blood
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Lupus Erythematosus, Systemic / blood
  • Lupus Erythematosus, Systemic / immunology
  • Lupus Erythematosus, Systemic / metabolism*
  • Lupus Erythematosus, Systemic / pathology
  • Lymphocyte Activation*
  • Membrane Glycoproteins / agonists
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism
  • Myeloid Differentiation Factor 88 / agonists
  • Myeloid Differentiation Factor 88 / genetics
  • Myeloid Differentiation Factor 88 / metabolism
  • Phosphorylation
  • Protein Processing, Post-Translational
  • Protein-Tyrosine Kinases / blood
  • Protein-Tyrosine Kinases / metabolism*
  • Receptors, IgG / blood
  • Receptors, IgG / metabolism*
  • Receptors, Interleukin-1 / agonists
  • Receptors, Interleukin-1 / genetics
  • Receptors, Interleukin-1 / metabolism
  • Syk Kinase
  • Toll-Like Receptors / agonists*
  • Toll-Like Receptors / genetics
  • Toll-Like Receptors / metabolism
  • Up-Regulation

Substances

  • Antigen-Antibody Complex
  • Biomarkers
  • Complement Membrane Attack Complex
  • FCGR3A protein, human
  • HMGB1 Protein
  • HMGB1 protein, human
  • IFNG protein, human
  • IL17A protein, human
  • Interleukin-17
  • Intracellular Signaling Peptides and Proteins
  • MYD88 protein, human
  • Membrane Glycoproteins
  • Myeloid Differentiation Factor 88
  • Receptors, IgG
  • Receptors, Interleukin-1
  • TIRAP protein, human
  • Toll-Like Receptors
  • Interferon-gamma
  • Protein-Tyrosine Kinases
  • SYK protein, human
  • Syk Kinase