title: HTLV-1 propels thymic human T cell development in "human immune system" Rag2⁻/⁻ gamma c⁻/⁻ mice.
abstract: Alteration of early haematopoietic development is thought to be responsible for the onset of immature leukemias and lymphomas. We have previously demonstrated that Tax(HTLV-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⁻/⁻γ(c)⁻/⁻ 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⁻/⁻γ(c)⁻/⁻ animal model to elucidate the initial steps of the leukemogenic process induced by HTLV-1.
authors: Virologie Humaine, INSERM-U758, Lyon, France.
authors: Julien
authors: J
authors: Villaudy
authors: Mélanie
authors: M
authors: Wencker
authors: Nicolas
authors: N
authors: Gadot
authors: Nicolas A
authors: NA
authors: Gillet
authors: Jean-Yves
authors: JY
authors: Scoazec
authors: Louis
authors: L
authors: Gazzolo
authors: Markus G
authors: MG
authors: Manz
authors: Charles R M
authors: CR
authors: Bangham
authors: Madeleine Duc
authors: MD
authors: Dodon
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics; D004195:Disease Models, Animal; D015490:HTLV-I Infections / Q000276:immunology* / Q000473:pathology; D018380:Hematopoietic Stem Cell Transplantation; D015368:Human T-lymphotropic virus 1 / Q000502:physiology*; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000209:etiology; D051379:Mice; D060168:Thymocytes / Q000502:physiology* / Q000821:virology; D018183:Transplantation Chimera / Q000276:immunology; D014183:Transplantation, Heterologous; D019562:Viral Load
chemical_list: D004268:DNA-Binding Proteins; C499308:Rag2 protein, mouse