Human T-cell leukaemia virus type 1 (HTLV-1), is the etiologic agent of Adult T-cell Leukaemia (ATL), characterized by a clonal expansion of CD4+ T-cells. This leukaemia appears in adult individuals who have been infected by breast-feeding during the neonatal period. Recent studies have shown that disruption of haematopoiesis is very often at the origin of a leukaemic process. To that regard, the emergence of ATL might be associated with the disruption of abT-cell development in human thymus.
Early abT-cell development is dependent on the expression of a pre-TCR at the membrane of a small subset of immature single positive thymocytes (CD4 ISP). Pre-TCR is made up of the newly rearranged TCR b-chain and the pre-TCRa (pTa) invariant chain, associated with CD3 molecules. Such a complex activates signalling pathways critical for survival, proliferation, and differentiation of T-cells in a process also referred to as b-selection checkpoint. The assembly of a functional pre-TCR is dependent on pTa, which is regulated at the transcriptional level by E2A proteins, belonging to the bHLH family of transcription factors. Notably, inhibition of the expression of E2A proteins during thymocyte development has been associated with leukaemia in mice.
The regulatory protein Tax of HTLV-1 is mainly known as a transcriptional activator. It is also able to repress gene transcription through the inhibition of the activity of bHLH proteins by sequestering CBP-p300 co-activators of the basal transcription machinery. Thus, we hypothesize that Tax expression in CD4 ISP thymocytes lead to decreased pTa expression, thus defining a critical event for ATL development. We indeed demonstrated that Tax efficiently suppresses the E47-mediated activation of the pTa promoter. We also find that the amount of pTa transcripts decreases in lentivirally Tax-transduced human MOLT4 T cells, which constitutively express the pTa gene. Finally, the expression of Tax in human CD4ISP thymocyts leads to a decrease of pTa gene transcription, but does not modify the level of E47 (an E2A protein) transcripts. Collectively, these observations indicate that Tax, by silencing E proteins, down-regulates the pTa gene transcription. They further provide evidence that Tax interferes with an important checkpoint during abT-cell development in the thymus.
