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 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.

TCF1 and LEF1 act as T-cell intrinsic HTLV-1 antagonists by targeting Tax

“…Therefore, our results also imply an interesting possibility that HTLV-1 might achieve its expansion as infected T cells differentiate or even by driving differentiation of infected T cells to reduce TCF1/LEF1 expression. Indeed, a recent report using humanized mice showed altered T-cell development upon HTLV-1 infection in that the mature SP population, instead of immature DN or DP, becomes dominant in the thymus (40). This finding suggests that thymocytes are propelled to develop by HTLV-1 or the virus selectively expands in the more differentiated subsets.…”

Les souris ne sont pas des hommes et pourtant…

“…L'infection, attestée par une charge provirale élevée dans les thymocytes et les splénocytes humains, perturbe la maturation des thymocytes, provoque une augmentation du nombre de lymphocytes T dans les organes périphériques et induit des pathologies caractéristiques de l'ATL. Ces résultats suggèrent que, chez l'homme, l'infection par HTLV-1 des thymocytes immatures est un événement favorisant le développement de leucémies/lymphomes [27].…”

An animal model of adult T-cell leukemia: humanized mice with HTLV-1–specific immunity

“…9 To reproduce the pathogenesis of ATL, a number of mouse models have been developed, including transgenic or xenografted/ humanized mice. [10][11][12][13][14][15][16][17][18] One such model is the Tax-transgenic mouse, which expresses Tax under the control of the Lck promoter. This model restricts Tax expression to developing thymocytes, resulting in characteristic ATL-like phenotypes.…”

“…17,21,22 Recent studies on HTLV-1 infection in humanized mouse models successfully reproduced HTLV-1-associated T-cell lymphomas 16,17 ; however, these models did not accurately recreate human immune responses against HTLV-1.…”