Upregulation of innate signaling upon ligation of FcγRIIIa by immune complexes in Human CD4+ T-cells

Abstract

Abstract Over the past two decades, role of Fc-receptor (FcR) signaling in CD4+ T-cell responses has been overlooked. Whether FcRs signaling in CD4+ T-cells contribute to tolerance breakdown and nucleic acid sensing remain an open question. We earlier reported that the FcγRIIIa cosignaling differentiates human naïve CD4+ T-cells in the absence of CD28 cosigning (JBC, 5128: 2016). We now show that the FcγRIIIa signaling upregulate the expression of nucleic acid sensing toll-like receptors (NA-TLRs) in naïve human CD4+ T-cells. TLR9 accumulate as a full length 120-kDa protein on the cell surface (revision in JI). TLR9 bound to CpG ODN 2006 and localized with FcγRIIIa on the cell surface. Subcellular location of the TLR9 discriminate between modified self-nucleic acid from encapsulated viral nucleic acids. FcγRIIIa signal relocated MyD88 and HMGB1 proteins underneath cell surface with TLR9 forming “myddosomes”. RNA-seq data showed upregulation of several key pathways, which are normally observed during innate immune responses. FcγRIIIa signal upregulated RNA transcripts encoding for IL-1α, IL-1β, IL-2, IL-17A, IL-22, IL-23, IL-31RA, and IL-34 cytokines. Transcripts from IFN subsets, IL-27, IFNι-2, IFNι-3, IFNω, IFNβ, IFNα and IFN inducible genes were upregulated. TLR9 signaling drives the production of IFN-γ, IL-17A, IL-21, ICOS and Bcl6 proteins. Statistically significant increase in the genes from cellular response to DNA damage; RNA-binding; and ERK-signaling was observed. lncRNAs populate exosomes and also regulate TLRs, which were unregulated by FcγRIIIa signal. Our data show that the FcγRIIIa drives innate signaling pathways often observed during inflammation, which may contribute to the naive CD4+ T-cell differentiation.