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Blood, 1 May 2008, Vol. 111, No. 9, pp. 4741-4751. Prepublished online as a Blood First Edition Paper on February 14, 2008; DOI 10.1182/blood-2007-10-115220.
Submitted October 1, 2007
Institute of Clinical and Molecular Virology, Friedrich Alexander-Universitat Erlangen-Nurnberg, Erlangen, Germany * Corresponding author; email: grassmann{at}viro.med.uni-erlangen.de.
Human T-cell leukemia virus type 1 (HTLV-1), the cause of adult T-cell leukemia, stimulates the growth of infected T-cells in cultures and in non-leukemic patients. In the latter HTLV-1 is found in long-term persisting T-cell clones. The persistence of normal T-cells is controlled by the growth-stimulating and antiapoptotic functions of costimulatory receptors, while the growth-stimulating HTLV-1 functions are mediated by the viral oncoprotein Tax. Here we analyzed the impact of Tax on costimulatory receptors in T-cells with repressible Tax and found that among these receptors 4-1BB (TNFRSF9/CD137/ILA) was induced most strongly. Upregulated 4-1BB expression was a consistent feature of all HTLV-1-infected cell lines, whether patient-derived or in-vitro-transformed. Tax was sufficient to induce the expression of the endogenous 4-1BB gene in uninfected T-cells and it strongly activated (45-fold) the 4-1BB promoter via a single NF-
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| Copyright © 2008 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
B site. The ligand of 4-1BB was also found on transformed T-cell lines opening up the possibility of autostimulation. Moreover, 4-1BB expression in patients' lymphocytes ex vivo correlated with Tax expression, strongly suggesting Tax-mediated 4-1BB activation in vivo. Thus, 4-1BB upregulation by Tax could contribute to growth, survival and clonal expansion of the infected cells during persistence and disease.
