Y. Galley et al., JUN NH2-TERMINAL KINASE IS CONSTITUTIVELY ACTIVATED IN T-CELLS TRANSFORMED BY THE INTRACELLULAR PARASITE THEILERIA-PARVA, Proceedings of the National Academy of Sciences of the United Statesof America, 94(10), 1997, pp. 5119-5124
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.