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* Laboratoire d'Immunologie, Centre de Recherches du Centre Hospitalier de l'Université de Montréal, Saint-Luc,
Department of Microbiology and Immunology and
Department of Medicine, Division of Experimental Medicine, McGill University,
Département de Microbiologie et Immunologie, Faculté de Médecine, Université de Montréal, and
¶ Institut National de la Santé et de la Recherche Médicale Unité 743, Centre de Recherche-Centre Hospitalier de l'Université de Montréal, Université de Montréal, Montréal, Québec, Canada
TLRs constitute a first set of sensors that detect viral nucleic acids including dsRNA which triggers TLR3. We report the early, direct, and detrimental effect of polyinosine-polycytidilic acid treatment on T cell development. Inhibition of thymopoiesis was targeted to several thymocyte subpopulations. First, both a blockade of the double negative (DN)1-DN2 transition and a severe down-regulation of DN3-DN4 thymocyte proliferation were observed. In addition, an important decrease in the absolute numbers of double-positive thymocytes, concomitant with an increase in frequencies of apoptotic cells in this population were shown. This inhibition of thymopoiesis resulted in a reduced thymic output, as evidenced by a drop of the absolute numbers of naive T cells and TCR excision circles levels. The decrease in thymic cellularity and defects in thymic development were severely reduced, but not completely abolished in IFN-
/βR–/– mice, showing a direct contribution of type I IFNs, known to be massively up-regulated in viral infections, to the inhibition of T cell development. Strikingly, the TCR repertoire in treated mice was biased toward shorter CDR3 lengths as a result of a decreased expression of TdT and Rag2. However, thymic integrity remained intact since thymopoiesis was restored both quantitatively and qualitatively 14 days after the cessation of polyinosine-polycytidilic acid treatment. These results demonstrate a novel immunomodulatory role for virally encoded TLR ligands and RNA sensors; they further illustrate the diversity of mechanisms that viruses use to interfere with the development of a pathogen-specific immune responses.
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 to R.-P.S. from the Canadian Institutes of Health Research (CIHR) and from the Canadian Network for Vaccine and Immunotherapeutics. R.-P.S. is the Canada Research Chair in Human Immunology.
2 A.A. and N.K. contributed equally to this work.
3 Address correspondence and reprint request 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: DP, double positive; DN, double negative; FTOC, fetal thymic organ culture; MFI, mean fluorescence intensity; poly(I:C), polyinosine-polycytidylic acid; SP, single positive; TREC, TCR excision circle; mLN, mesenteric lymph node; RTE, recent thymic emigrant; TEC, thymic epithelial cell.
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