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

CD4(+) T-cells in systemic lupus erythematosus (SLE) patients show altered T-cell receptor signaling, which utilizes Fc-receptor gamma-chain FcR gamma-Syk. A role for Fc gamma RIIIa 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 Fc gamma RIIIa 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-gamma(high) CD4(+) T-cells in vitro. Cytokines IL-1 beta, IL-6, TGF-beta 1, 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-gamma and IL-17A. This Fc gamma RIIIa-mediated co-signal differentially up-regulated the expression of IFN pathway genes compared with CD28 co-signal. Fc gamma RIIIa-pSyk upregulated 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 Fc gamma RIIIa-pSyk signal in modulating adaptive immune responses.