Villaudy, Julien Wencker, Mélanie Gadot, Nicolas Gillet, Nicolas A. Scoazec, Jean-Yves Gazzolo, Louis Manz, Markus G. Bangham, Charles R. M. Duc Dodon, Madeleine 2011-09-01 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. application/pdf https://susi.usi.ch/global/documents/318944 https://n2t.net/ark:/12658/srd1318944 https://susi.usi.ch/documents/318944/files/Villaudry_PP_2011.pdf eng info:eu-repo/semantics/altIdentifier/doi/10.1371/journal.ppat.1002231 info:eu-repo/semantics/altIdentifier/ark/12658/srd1318944 info:eu-repo/semantics/openAccess CC BY Plos pathogens. - 2011, vol. 7, no. 9, p. e1002231 info:eu-repo/classification/udc/61 HTLV-1 propels thymic human T cell development in “human immune system” Rag2-/- gamma c-/- Mice http://purl.org/coar/resource_type/c_6501