HTLV-1 propels thymic human T cell development in “human immune system” Rag2-/- gamma c-/- Mice
- Villaudy, Julien Virologie Humaine, INSERM-U758, Lyon, France - Ecole Normale Supérieure, Lyon, France - UMS3444 BioSciences Lyon-Gerland, Lyon, France
- Wencker, Mélanie Virologie Humaine, INSERM-U758, Lyon, France - Ecole Normale Supérieure, Lyon, France - UMS3444 BioSciences Lyon-Gerland, Lyon, France - Cancer Research UK, London Research Institute and King's College, London, United Kingdom
- Gadot, Nicolas Anipath, UFR Médecine Lyon-RTH Laennec, Lyon, France
- Gillet, Nicolas A. Department of Immunology, Wright-Fleming Institute, Imperial College London, London, United Kingdom - Molecular and Cellular Epigenetics, Interdisciplinary Cluster for Applied Genoproteomics (GIGA) of University of Liège (ULg), Liège, Belgium
- Scoazec, Jean-Yves Anipath, UFR Médecine Lyon-RTH Laennec, Lyon, France
- Gazzolo, Louis Virologie Humaine, INSERM-U758, Lyon, France - Ecole Normale Supérieure, Lyon, France - UMS3444 BioSciences Lyon-Gerland, Lyon, France
- Manz, Markus G. Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland - University Hospital Zürich, Division of Hematology, Zürich, Switzerland
- Bangham, Charles R. M. Department of Immunology, Wright-Fleming Institute, Imperial College London, London, United Kingdom
- Duc Dodon, Madeleine Virologie Humaine, INSERM-U758, Lyon, France - Ecole Normale Supérieure, Lyon, France - UMS3444 BioSciences Lyon-Gerland, Lyon, France
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01.09.2011
Published in:
- Plos pathogens. - 2011, vol. 7, no. 9, p. e1002231
English
Alteration of early haematopoietic development is thought to be responsible for the onset of immature leukemias and lymphomas. We have previously demonstrated that TaxHTLV-1 interferes with ß- selection, an important checkpoint of early thymopoiesis, indicating that human T-cell leukemia virus type 1 (HTLV-1) infection has the potential to perturb thymic human αβ T-cell development. To verify that inference and to clarify the impact of HTLV-1 infection on human T-cell development, we investigated the in vivo effects of HTLV-1 infection in a “Human Immune System” (HIS) Rag2-/-γc-/- mouse model. These mice were infected with HTLV-1, at a time when the three main subpopulations of human thymocytes have been detected. In all but two inoculated mice, the HTLV-1 provirus was found integrated in thymocytes; the proviral load increased with the length of the infection period. In the HTLV-1-infected mice we observed alterations in human T-cell development, the extent of which correlated with the proviral load. Thus, in the thymus of HTLV-1-infected HIS Rag2-/-γc-/- mice, mature single-positive (SP) CD4+ and CD8+ cells were most numerous, at the expense of immature and double-positive (DP) thymocytes. These SP cells also accumulated in the spleen. Human lymphocytes from thymus and spleen were activated, as shown by the expression of CD25: this activation was correlated with the presence of tax mRNA and with increased expression of NF-kB dependent genes such as bfl-1, an anti-apoptotic gene, in thymocytes. Finally, hepato-splenomegaly, lymphadenopathy and lymphoma/thymoma, in which Tax was detected, were observed in HTLV-1-infected mice, several months after HTLV-1 infection. These results demonstrate the potential of the HIS Rag2-/-γc-/- animal model to elucidate the initial steps of the leukemogenic process induced by HTLV-1.
- Language
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- English
- Classification
- Medicine
- License
- License undefined
- Identifiers
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- RERO DOC 326641
- DOI 10.1371/journal.ppat.1002231
- ARK ark:/12658/srd1318944
- Persistent URL
- https://n2t.net/ark:/12658/srd1318944
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