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TLR3 Ligand Polyinosinic:Polycytidylic Acid Induces IL-17A and IL-21 Synthesis in Human Th Cells¹

Christian K. Holm^2,*,, Charlotte C. Petersen^*, Malene Hvid^*, Line Petersen^*, Søren R. Paludan^*, Bent Deleuran^*, and Marianne Hokland^*

^* Institute of Medical Microbiology and Immunology, University of Aarhus, Aarhus, Denmark; and Laboratory of Immunohematology, Department of Hematology and Department of Rheumatology, Aarhus University Hospital, Aarhus, Denmark

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 T_H17. 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Karen Elise Jensen Foundation; the University of Aarhus Research Foundation, the Faculty of Health, University of Aarhus; the Aage Bang Foundation; the Danish Rheumatism Association; the Danish Psoriasis Association, and Max and Inger Wörzner Mindelegat.

² Address correspondence and reprint requests to Dr. Christian Kanstrup Holm, Institute of Medical Microbiology and Immunology, University of Aarhus, Aarhus, Denmark. E-mail address: chol{at}immunology.au.dk

³ Abbreviations used in this paper: SAPK, stress-associated protein kinase; IRF, IFN response family; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; NBD, Nemo-binding domain binding peptide; RQ-PCR, quantitative RT-PCR; fwd, forward; rev, reverse; TRAF, TNFR-associated kinase; poly(I:C), polyinosinic:polycytidylic acid; RORC, retinoic acid receptor-related orphan receptor C.