Fc{gamma}RIIIa Signaling Modulates Endosomal TLR Responses in Human CD4+ T Cells [AUTOIMMUNITY]

Recognition of Ab-opsonized pathogens by immune cells triggers both TLR and Fc receptor signaling. Fc receptors endocytose modified nucleic acids bound to Abs and deliver them to endosomes, where they are recognized by nucleic acid–sensing TLRs (NA-TLRs). We show that in CD4⁺ T cells, NA-TLRs, TLR3, TLR8, and TLR9 are upregulated by FcRIIIa-pSyk cosignaling and localize with FcRIIIa on the cell surface. TLR9 accumulates on the cell surface, where it recognizes CpG oligonucleotide 2006. Subcellular location of NA-TLRs is a key determinant in discriminating self versus viral nucleic acid. Hydroxychloroquine used for treating systemic lupus erythematosus and a Syk inhibitor blocked NA-TLR localization with FcRIIIa. Engaging TLR9 with CpG oligonucleotide contributes to the development of IL17A⁺ and IL-21⁺ populations. RNA-sequencing analysis showed upregulation of proinflammatory cytokines, NF-B signaling, and heat shock protein pathway RNA transcripts. These data suggest a role for FcRIIIa-pSyk cosignaling in modulating NA-TLR responses in human CD4⁺ T cells by affecting the amounts and cellular distribution. These events are important for understanding of autoimmune pathology.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2rXp414
via IFTTT