Human T-Cell Leukemia Virus Type 1 Tax Protein Down-Regulates Pre-T-Cell Receptor Alpha Gene Transcription in Human Immature Thymocytes

Abstract

The human pre-T-cell receptor alpha (TCRα; pTα) gene encodes a polypeptide which associates with the TCRβ chain and CD3 molecules to form the pre-TCR complex. The surface expression of the pre-TCR is pTα dependent, and signaling through this complex triggers an early αβ T-cell developmental checkpoint inside the thymus, known as β-selection. E2A transcription factors, which are involved at multiple stages of T-cell development, regulate the transcription of the pTα gene. Here we show that the regulatory protein Tax of the human T-cell leukemia virus type 1 (HTLV-1) efficiently suppresses the E47-mediated activation of the pTα promoter. Furthermore, we report that in Tax lentivirally transduced human MOLT-4 T cells, which constitutively express the pTα gene, the amount of pTα transcripts decreases. Such a decrease is not observed in MOLT-4 cells transduced by a vector encoding the Tax mutant K88A, which is unable to interact with p300. These data underline that Tax inhibits pTα transcription by recruiting this coactivator. Finally, we show that the expression of Tax in human immature thymocytes results in a decrease of pTα gene transcription but does not modify the level of E47 transcripts. These observations indicate that Tax, by silencing E proteins, down-regulates pTα gene transcription during early thymocyte development. They further provide evidence that Tax can interfere with an important checkpoint during T-cell differentiation in the thymus.