Induction of signalling anergy via the T-cell receptor in cultured Jurkat T cells by pre-exposure to a filarial nematode secreted product

Filarial nematodes constitute major causes of morbidity in the Tropics. The worms have a life-span exceeding Jive years, a longevity which is consider ed to reflect at least in part, their ability to interfere with host lympho cyte responsiveness. To date the molecular mechanisms underlying this abili ty have not been defined but we now demonstrate that ES-62, a phosphorylcho line (PC)-containing glycoprotein released by the rodent filarial parasite Acanthocheilonema viteae, is able to render Jurkat T cells anergic to intra cellular signalling via the antigen receptor (TCR). In particular, ES-62 ac ts by modulating activation of the tyrosine kinases Fyn, Lck and ZAP-70 lea ding to selective disruption of TCR coupling to the phospholipase D, protei n kinase C, phosphoinositide-3-kinase and RasMAPkinase signalling cascades. These cascades are kev elements in the transduction of transcriptional and proliferative signals following ligation of TCR. As PC-containing secreted products (PC-ES) are also released by human filarial parasites, our data s uggest that PC-ES may play a role in the induction of T lymphocyte hyporesp onsiveness observed during filarial infections.