HTLV-1 Tax-Mediated Inhibition of FOXO3a Activity Is Critical for the Persistence of Terminally Differentiated CD4+ T Cells

PLoS Pathogens

Rongtuan Lin¹  Cindy Chiang²  David Olagnier²  Samar Bel Hadj²  Jean-Pierre Routy²  John Hiscott²  Julien van Grevenynghe²  Xiaoying Han³  Courtney Steel³  Alexandre Sze³ 

[1] Immunodeficiency Service and Division of Haematology, Royal Victoria Hospital, McGill University Health Center, McGill University, Montreal, Quebec, Canada;Lady Davis Institute-Jewish General Hospital, McGill University, Montreal, Quebec, Canada;VGTI Florida, Port St. Lucie, Florida, United States of America

关键词: T cells;    HTLV-1;    Cell differentiation;    Cell staining;    Gene expression;    Small interfering RNAs;    DNA transcription;    Apoptosis;   

DOI  :  10.1371/journal.ppat.1004575

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

The mechanisms involved in the persistence of activated CD4+ T lymphocytes following primary human T leukemia/lymphoma virus type 1 (HTLV-1) infection remain unclear. Here, we demonstrate that the HTLV-1 Tax oncoprotein modulates phosphorylation and transcriptional activity of the FOXO3a transcription factor, via upstream activation of the AKT pathway. De novo HTLV-1 infection of CD4+ T cells or direct lentiviral-mediated introduction of Tax led to AKT activation and AKT-dependent inactivation of FOXO3a, via phosphorylation of residues Ser253 and Thr32. Inhibition of FOXO3a signalling led to the long-term survival of a population of highly activated, terminally differentiated CD4+Tax+CD27negCCR7neg T cells that maintained the capacity to disseminate infectious HTLV-1. CD4+ T cell persistence was reversed by chemical inhibition of AKT activity, lentiviral-mediated expression of a dominant-negative form of FOXO3a or by specific small interfering RNA (siRNA)-mediated silencing of FOXO3a. Overall this study provides new mechanistic insight into the strategies used by HTLV-1 to increase long-term maintenance of Tax+CD4+ T lymphocytes during the early stages of HTLV-1 pathogenesis.

【 授权许可】

CC BY