Background T cells contribute to the disease process in systemic lupus erythematosus (SLE) (1-3). IFN-γ is a cytokine produced by the Th1 subset that drives autoimmune pathology (4, 5). IFN-γ produced during Th1 response via autocrine process regulates its own expression and also of the transcriptional regulator T-bet (Tbx21). In an autoimmune pathology, CD4+ T cells are activated in the absence of co-stimulatory CD28 signal. The underlying mechanism of this activation is unknown. We show that engagement of low affinity FcγRIIIa from ligation by immune complexes (ICs) provide a co-stimulatory signal that drive the generation of a high IFN-g producing subset and a Th17 like population. We for the first time establish a role for FcgRIIIa in modulating the adaptive immune response. IFN-γ is a key cytokine that enhance B cell response, activate macrophages, and chromatin remodeling
Objectives To investigate the role of ICs in CD4+ naïve T cells differentiation.
Methods We activated peripheral naïve CD4+CD45RA+ T cells in vitro using ICs purified from SLE plasma. Thereafter, we differentiated these cells in the presence of IL-2 (2 U/ml) and IL-12 (50 U/ml) cytokines. We then examined the production of IFN-γ by flow, and in the culture supernatants. Gene transcripts of ifng and Tbx21 were analyzed using qRT-PCR. IFN pathway genes were analyzed using PCR-array. We further examined the role of ICs in the differentiation Th17 cells, in the presence of IL-1b, IL-6, IL23, and TGFβ-1 cytokines.
Results We show that upon activation by ICs human peripheral CD4+ T-lymphocytes differentiate into a Th1 like cell phenotype that produces high levels of IFN-γ and express T-bet. All five donors analyzed demonstrate increases in ifng and Tbx21 transcripts. IFN pathway genes showed several folds from 3 to 20-fold increase in the transcript's associated with IFN signaling. One donor also showed expression of type 1 IFN transcripts that were further up-regulated from ICs signaling. The presence of type 1-IFN transcripts in CD4+ T cells has not been previously demonstrated. The co-stimulatory signal by ICs was more potent than CD28 for the production of IFN-g. In the Th17 polarizing milieu, three subsets of population was observed, IFN-γ+IL17A-, IFN-γ-IL-17A+, and IFN-γ+IL-17+. Increase in RORC transcripts were also observed.
Conclusions We for the first time demonstrate a role for FcgRIIIa in the differentiation of the human peripheral naïve CD4+ T cells. ICs by ligating FcgRIIIa generated both Th1 and Th17 like populations, thus suggesting a role in autoimmune pathology.
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Disclosure of Interest None declared
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