Reversible blockade of thymic output: an inherent part of TLR ligand-mediated immune response.
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-alpha/betaR(-/-) 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.
Démoulins
Thomas
T
Laboratoire d'Immunologie, Centre de Recherches du Centre Hospitalier de l'Université de Montréal, Saint-Luc, Canada.
Abdallah
Ali
A
Kettaf
Nadia
N
Baron
Marie-Laurence
ML
Gerarduzzi
Casimiro
C
Gauchat
Dominique
D
Gratton
Sophie
S
Sékaly
Rafick-Pierre
RP
D000818:Animals; D000998:Antiviral Agents / Q000276:immunology*; D017209:Apoptosis / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011070:Poly I-C / Q000276:immunology*; D016133:Polymerase Chain Reaction; D012367:RNA, Viral / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D013950:Thymus Gland / Q000254:growth & development / Q000276:immunology* / Q000473:pathology; D051193:Toll-Like Receptors / Q000276:immunology*
D000998:Antiviral Agents; D008024:Ligands; D012367:RNA, Viral; D011948:Receptors, Antigen, T-Cell; D051193:Toll-Like Receptors; D011070:Poly I-C