HTLV-1 propels thymic human T cell development in textquotedblhuman immune systemtextquotedbl Rag2(-)/(-) gamma c(-)/(-) mice.

J. Villaudy, M. Wencker, N. Gadot, N. Gillet, J.-Y. Scoazec, L. Gazzolo, M. G. Manz, C. R. M. Bangham, M. D. Dodon

Research output: Contribution to journalArticlepeer-review

Abstract

[en] 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 alphabeta 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 textquotedblHuman Immune Systemtextquotedbl (HIS) Rag2(-)/(-)gamma(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(-)/(-)gammac(-)/(-) 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(-)/(-)gamma(c)(-)/(-) animal model to elucidate the initial steps of the leukemogenic process induced by HTLV-1.
Original languageEnglish
Pages (from-to)e1002231
JournalPlos Pathogens
Volume7
Issue number9
DOIs
Publication statusPublished - 2011
Externally publishedYes

Keywords

  • Sciences de la santé humaine => Oncologie
  • Animals
  • DNA-Binding Proteins/genetics
  • Disease Models, Animal
  • HTLV-I Infections/immunology/pathology
  • Hematopoietic Stem Cell Transplantation
  • Human T-lymphotropic virus 1/physiology
  • Humans
  • Leukemia-Lymphoma, Adult T-Cell/etiology
  • Mice
  • Thymocytes/physiology/virology
  • Transplantation Chimera/immunology
  • Transplantation, Heterologous
  • Viral Load

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