TLR3 Ligand Polyinosinic:Polycytidylic Acid Induces IL-17A and IL-21 Synthesis in Human Th Cells

Abstract

TLR3 and TLR9 recognize the pathogen-associated microbial patterns dsRNA and unmethylated DNA, respectively. The recent discovery that these receptors also recognize endogenous ligands from necrotic material has drawn increased attention to their involvement in autoimmunity. Th cell cytokines IL-17A and IL-21 have been assigned with pivotal roles in the regulation of such autoimmune diseases. IL-17A is the hallmark cytokine of the recently discovered proinflammatory Th cell subset TH17. By contrast, the expression of IL-21 does not seem to be limited to a single distinct Th cell subset. We investigated the expression of IL-17A and IL-21 in human CD4+ T cells in response to stimulation with the TLR3 ligand polyinosinic:polycytidylic acid (poly(I:C)) and the TLR9 ligand CpG. We discovered that poly(I:C) induced synthesis of both IL-17A and IL-21. Moreover, we found that poly(I:C) was able to drive the differentiation of naive Th cells into an IL-21 but not into an IL-17A-producing phenotype and did this without affecting the levels of transcription factors T-bet, GATA-3, or retinoic acid receptor-related orphan receptor C. Finally, we found that the IL-21-producing cells that were differentiated in response to poly(I:C) expressed the chemokine receptor CXCR3, which is important in the recruitment of T cells into inflamed joints in rheumatoid arthritis. This is the first report to show that the TLR3 ligand poly(I:C) can directly induce the synthesis of IL-17A and IL-21 and drive differentiation of human naive CD4+ T cells.

Molecular evidence for the involvement of RORα and RORγ in immune response in teleost

“…4). In mammal and fish, poly I:C has been widely used to mimic viral infection [28,29]. Accordingly, our data point to the different roles of grass carp RORa and RORg in immune response induced by specific pathogen-associated patterns.…”

Defining CD4 T Cell Memory by the Epigenetic Landscape of CpG DNA Methylation

“…Previous studies have shown that TLR3 is costimulatory for CD4 T cells (58, 59) and activation through both CD3 and TLR3 leads to expression of IL-17A, IL-21 (59), CCL3, CCL4, CCL5 and granzyme B (58). While TLR3 signaling is not sufficient to induce proliferation of T cells with anti-CD3, the addition of a TLR3 stimulus enhances CD3/CD28 costimulation-induced proliferation (58).…”

Critical Role of IRF-8 in Negative Regulation of TLR3 Expression by Src Homology 2 Domain-Containing Protein Tyrosine Phosphatase-2 Activity in Human Myeloid Dendritic Cells

“…Moreover, a new TLR3-dependent route that induces the synthesis of CD4 + T cell proinflammatory cytokines has been recently reported, extending TLR3 functions to autoimmune diseases (42). Therefore, it is possible that regulatory mechanisms described in this study can be also extended to different cell types.…”