Jun NH₂-terminal kinase is constitutively activated in T cells transformed by the intracellular parasiteTheileria parva

Abstract

When T cells become infected by the parasite Theileria parva, they acquire a transformed phenotype and no longer require antigen-specific stimulation or exogenous growth factors. This is accompanied by constitutive interleukin 2 (IL-2) and IL-2 receptor expression. Transformation can be reversed entirely by elimination of the parasites using the specific drug BW720c. Extracellular signal-regulated kinase and jun NH2-terminal kinase (JNK) are members of the mitogen-activated protein kinase family, which play a central role in the regulation of cellular differentiation and proliferation and also participate in the regulation of IL-2 and IL-2 receptor gene expression. T. parva was found to induce an unorthodox pattern of mitogen-activated protein kinase expression in infected T cells. JNK-1 and JNK-2 are constitutively active in a parasite-dependent manner, but have altered properties. In contrast, extracellular signal-regulated kinase-2 is not activated even though its activation pathway is functionally intact. Different components of the T cell receptor (TCR)-dependent signal transduction pathways also were examined. The TCR or CD3 chains were found not to be phosphorylated and T. parva-transformed T cells were resistant to inhibitors that block the early steps of T cell activation. Compounds that inhibit the progression of T cells to proliferation, however, were inhibitory. Our data provide the first example, to our knowledge, for parasite-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 pathways to induce continuous proliferation.

Constitutive PI3-K activity is essential for proliferation, but not survival, of Theileria parva-transformed B cells

“…An obvious candidate could be mTOR, a known downstream effector of PI3-K and a mediator of S-phase entry through p70S6k and eIF4E (for a recent review, see Thomas et al, 1997). Consistent with this notion is that rapamycin, an inhibitor of mTOR, blocks proliferation of T. parva-infected T cells (Galley et al, 1997) and, partially, proliferation of TpM409 and T. annulata-infected macrophages (data not shown).…”

“…We demonstrate that one mechanism by which PI3-K contributes to the continued proliferation of T. parva-infected B cells is via the induction of a granulocyte±monocyte colony-stimulating factor (GM-CSF)-dependent autocrine loop. As the proliferation of T. parva-infected T cells (Galley et al, 1997) and Theileria annulata-infected macrophages is also sensitive to PI3-K inhibition, we argue that induction of PI3-K-mediated autocrine/cytokine secretion may be a common feature of Theileria-transformed leucocytes.…”

“…Theileria-transformed leucocytes can be grown continuously in vitro without the addition of any exogenous growth factors, and form metastatic tumours when injected into scid mice (Fell et al, 1990). Infection of leucocytes with Theileria parasites is associated with constitutive activation of the transcription factor NF-kB (Ivanov et al, 1989) and of c-Jun N-terminal kinase (JNK; Chaussepied et al, 1998;Galley et al, 1997), which mediates upregulation of Fos and Jun protein levels and leads to permanent activation of the transcription factor AP-1 (Chaussepied et al, 1998).…”

Parasite-mediated nuclear factor κB regulation in lymphoproliferation caused byTheileria parva infection

“…The critical difference is that T. parva subverts the normal antigen signaling pathways to cause unlimited proliferation. T. parva infection bypasses the normal requirement for TCR activation as shown by the lack of TCR and CD3 phosphorylation in parasitized cells (42). Similarly, inhibition of early TCR-dependent signaling pathways using ascomycin or cyclosporin A to target calcineurin, or bisindolylmaleimide to block protein kinase C has no effect on T. parva-mediated proliferation (42).…”

Cytoplasmic sequestration of p53 promotes survival in leukocytes transformed by Theileria

“…Importantly, Theileria-induced transformation is reversible and parasite dependent, because specific elimination of the parasites from infected cells by the naphthoquinone derivate buparvaquone results in cessation of proliferation and apoptosis of the host cell (McHardy and Wekesa, 1985;Dobbelaere et al, 1988;Shayan et al, 1999). It is thus postulated that the parasite interferes with mitogenic pathways of the host cell, and several pathways, including the stress-dependent c-Jun kinase pathway (Galley et al, 1997), the mitogen-activated protein kinase pathway and the phosphoinositide-3 kinase/ protein kinase-B pathway, have been investigated (Heussler et al, 2001;Seitzer et al, 2006). Other studies indicated a direct parasite interaction with members of the nuclear factor-kB pathway, leading to the continuous translocation of active nuclear factor-kB to the nucleus of infected cells and thus the transcription of genes related to cell-cycle progression and suppression of apoptosis (Heussler et al, 2002).…”