Htlv-1 propels thymic human t cell development in human immune system rag2 -/- gamma c -/- mice

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. © 2011 villaudy et al.