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* Laboratoire d’Immunologie and
Unité Institut National de la Santé et de la Recherche Médicale 743, Immunologie Humaine, Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Hôpital Saint-Luc, Montréal, Québec, Canada;
Département de Microbiologie et d’Immunologie, Faculté de Médecine, Université de Montréal, Montréal, Québec, Canada;
Department of Microbiology and Immunology and
¶ Division of Experimental Medicine, Department of Medicine, McGill University, Montréal, Québec, Canada;
|| Sunnybrook Research Institute, Department of Molecular and Cellular Biology, Toronto, Ontario, Canada; and
# Université Catholique de Louvain, Christian de Duve Institute of Cellular Pathology, Brussels, Belgium
The interactions between TLRs and their ligands have profound immune modulation properties. Attention has focused mostly on the impact of TLR ligands on peripheral innate and adaptive immunity during viral infections, whereas little impact of TLR activation has been shown on thymic development. Here we show that treatment of murine fetal thymic organ cultures (FTOCs) with TLR3 or TLR7 ligands induced rapid expression of IFN-
and -β mRNA, hallmarks of acute and chronic viral infections. This resulted in an early developmental blockade, increased frequencies of apoptotic cells, and decreased proliferation of thymocytes, which led to an immediate decrease in cellularity. FTOCs infected with vesicular stomatitis virus, known to act through TLR7, were similarly affected. Down-regulation of IL-7R -chain expression, together with an increased expression of suppressor of cytokine signaling-1 and a concomitant decreased expression of the transcriptional regulator growth factor independence 1 were observed in TLR ligands or IFN-treated FTOCs. This indicates a role for these pathways in the observed changes in thymocyte development. Taken together, our data demonstrate that TLR activation and ensuing type I IFN production exert a deleterious effect on T cell development. Because TLR ligands are widely used as vaccine adjuvants, their immunomodulatory actions mediated mainly by IFN- suggested by our results should be taken in consideration.
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 grants from the Canadian Institutes of Health Research (to R.-P.S. and J.-C.Z.-P.), from the Canadian Network for Vaccine and Immunotherapeutics (to R.-P.S.), and from the Ontario HIV Treatment Network (to J.-C.Z.-P.). R.-P.S. is the Canada Research Chair in Human Immunology and J.-C.Z.-P. is the Canada Research Chair in Developmental Immunology. R.L.M.-M. is supported by a Postdoctoral Fellowship from the Ontario HIV Treatment Network.
2 M.-L.B. and D.G. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Rafick-Pierre Sékaly, Laboratoire d’Immunologie, Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Hôpital Saint-Luc, 264 René-Lévesque est, Bureau 1307, Montréal, Québec, Canada H2X 1P1. E-mail address: rafick-pierre.sekaly{at}umontreal.ca
4 Abbreviations used in this paper: IRF, IFN-regulatory factor; ODN, oligodeoxynucleotide; DL, delta like; DN, double negative; DP, double positive; FTOC, fetal thymic organ culture; Gfi, growth factor independence; MFI, mean fluorescence intensity; poly(I:C), polyinosine-polycytidylic acid; SOCS, suppressors of cytokine signaling; SP, single positive; VSV, vesicular stomatitis virus; WT, wild type.
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