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TLR Triggering on Tolerogenic Dendritic Cells Results in TLR2 Up-Regulation and a Reduced Proinflammatory Immune Program¹

Sonia Chamorro^*, Juan J. García-Vallejo^2,*, Wendy W. J. Unger^2,, Rosette J. Fernandes^*, Sven C. M. Bruijns^*, Sandra Laban, Bart O. Roep, Bert A. 't Hart and Yvette van Kooyk^3,*

^* Department of Molecular Cell Biology and Immunology, Vrije University Medical Center, Amsterdam, The Netherlands; Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands; and Department of Immunobiology, Biomedical Primate Research Center, Rijswijk, The Netherlands

Tolerogenic dendritic cells (TDC) offer a promising therapeutic potential to ameliorate autoimmune diseases. Reported to inhibit adaptive immune responses, little is known about their innate immunity receptor repertoire. In this study, we compared three types of human TDC (IL-10-DC, dexamethasone (DX)-DC, and 1,25(OH)₂D₃-DC) by their TLR expression and response to a set of TLR ligands. TDC are endowed with the same TLR set as standard monocyte-derived dendritic cells but respond differentially to the TLR stimuli Pam3CSK4, polyinosinic-polycytidylic acid, LPS, and flagellin. TDC expressed low or no IL-12-related cytokines and remarkably elevated IL-10 levels. Interestingly, only TDC up-regulated the expression of TLR2 upon stimulation. This boosted the tolerogenic potential of these cells, because IL-10 production was up-regulated in TLR2-stimulated, LPS-primed DX-DC, whereas IL-12 and TNF- secretion remained low. When comparing the TDC subsets, DX-DC and 1,25(OH)₂D₃-DC up-regulated TLR2 irrespective of the TLR triggered, whereas in IL-10-DC this effect was only mediated by LPS. Likewise, DX-DC and 1,25(OH)₂D₃-DC exhibited impaired ability to mature, reduced allostimulatory properties, and hampered capacity to induce Th1 differentiation. Therefore, both DX-DC and 1,25(OH)₂D₃-DC display the strongest tolerogenic and anti-inflammatory features and might be most suitable tools for the treatment of autoimmune diseases.

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 in part by Postdoctoral Fellowship Grant EX2005-010 from the Ministry of Education and Science of Spain (to S.C.), Multiple Sclerosis Research Grant 06-598 (to J.J.G.-V.), Juvenile Diabetes Research Foundation Program Grant 7-2005-877 (to W.W.J.U. and S.L.), and Netherlands Organization for Scientific Research (NWO) Pioneer Grant 900-02-002 (to J.J G.-V. and Y.v.K.).

² J.J.G.-V. and W.W.J.U. contributed equally to this article.

³ Address correspondence and reprint requests to Prof. Yvette van Kooyk, Department of Molecular Cell Biology and Immunology, Vrije University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands. E-mail address: y.vankooyk{at}vumc.nl

⁴ Abbreviations used in this paper: DC; dendritic cell; C_t, cycle threshold; DX, dexamethasone; GILZ, glucocorticoid-induced leucine zipper; ILT3, Ig-like-transcript 3; MHC-II, MHC class II; moDC, monocyte-derived DC; (1,25(OH)₂D₃, 1,25-dihydroxyvitamin D₃; OX40-L, OX40 ligand; poly(I:C), polyinosinic-polycytidylic acid; TDC, tolerogenic DC; Treg, regulatory T cell.