Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-51307
Villaudy, J; Wencker, M; Gadot, N; Gillet, N A; Scoazec, J Y; Gazzalo, L; Manz , M G; Bangham, C R; Dodon, M D (2011). HTLV-1 propels thymic human T cell development in "human immune system" Rag2⁻/⁻ gamma c⁻/⁻ mice. PLoS Pathogens, 7(9):e1002231.
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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.
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|Item Type:||Journal Article, refereed, original work|
|Communities & Collections:||04 Faculty of Medicine > University Hospital Zurich > Clinic for Hematology|
|DDC:||610 Medicine & health|
|Date:||1 September 2011|
|Deposited On:||25 Nov 2011 12:06|
|Last Modified:||10 Dec 2013 17:15|
|Publisher:||Public Library of Science|
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