JUN NH2-TERMINAL KINASE IS CONSTITUTIVELY ACTIVATED IN T-CELLS TRANSFORMED BY THE INTRACELLULAR PARASITE THEILERIA-PARVA

When T cells become infected by the parasite Theileria parva, they acq uire a transformed phenotype and no longer require antigen-specific st imulation or exogenous growth factors. This is accompanied by constitu tive interleukin 2 (IL-2) and IL-2 receptor expression. Transformation can be reversed entirely by elimination of the parasites using the sp ecific drug BW720c. Extracellular signal-regulated kinase and jun NH2- terminal kinase (JNK) are members of the mitogen-activated protein kin ase family, which play a central role in the regulation of cellular di fferentiation and proliferation and also participate in the regulation of IL-2 and IL-2 receptor gene expression. T. parva was found to indu ce an unorthodox pattern of mitogen-activated protein kinase expressio n in infected T cells. JNK-1 and JNK-2 are constitutively active in a parasite-dependent manner, but have altered properties. In contrast, e xtracellular signal-regulated kinase-2 is not activated even though it s activation pathway is functionally intact. Different components of t he T cell receptor (TCR)-dependent signal transduction pathways also w ere examined. The TCR zeta or CD3 epsilon chains were found not to be phosphorylated and T. parva-transformed T cells were resistant to inhi bitors that block the early steps of T cell activation. Compounds that inhibit the progression of T cells to proliferation, however, were in hibitory. Our data provide the first example, to our knowledge, for pa rasite-mediated JNK activation, and our findings strongly suggest that T. parva not only lifts the requirement for antigenic stimulation but also entirely bypasses early TCR-dependent signal transduction pathwa ys to induce continuous proliferation.