Altered expression of tyrosine kinases of the Src and Syk families in human T-cell leukemia virus type 1-infected T-cell lines

During the late phase of adult T-cell leukemia/lymphoma, a severe lymphopro liferative disorder caused by human T-cell leukemia virus type 1 (HTLV-1), leukemic cells no longer produce interleukin-2, Several studies have report ed the lack of the Src-like protein tyrosine kinase Lck and overexpression of Lyn and Fyn in these cells. In this report we demonstrate that, in addit ion to the downregulation of TCR, CD45, and Lck (which are key components o f T-cell activation), HTLV-1-infected cell lines demonstrate a large increa se of FynB, a Fyn isoform usually poorly expressed in T cells. Furthermore, similar to anergic T cells, Fyn is hyperactive in one of these HTLV-1-infe cted T-cell lines, probably as a consequence of Csk downregulation. A secon d family of two proteins, Zap-70 and Syk, relay the signal of T-cell activa tion. We demonstrate that in contrast to uninfected T cells, Zap-70 is abse nt in HTLV-1-infected T cells, whereas Syk is overexpressed, In searching f or the mechanism responsible for FynB overexpression and Zap-70 downregulat ion, we have investigated the ability of the Tax and Rex proteins to modula te Zap-70 expression and the alternative splicing mechanism which gives ris e to either FynB or FynT. By using Jurkat T cells stably transfected with t he tax and rex genes or inducibly expressing the tax gene, we found that th e expression of Rex was necessary to increase fynB expression, suggesting t hat Rex controls fyn gene splicing, Conversely, with the same Jurkat clones , we found that the expression of Tax but not Rex could downregulate Zap-70 expression. These results suggest that the effect of Tax and Rex must coop erate to deregulate the pathway of T cell activation in HTLV-1 infected T c ells.