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 five years, a longevity which is considered to reflect at least in part, their ability to interfere with host lymphocyte responsiveness. To date the molecular mechanisms underlying this ability have not been defined but we now demonstrate that ES-62, a phosphorylcholine (PC)-containing glycoprotein released by the rodent filarial parasite Acanthocheilonema viteae, is able to render Jurkat T cells anergic to intracellular signalling via the antigen receptor (TCR). In particular, ES-62 acts by modulating activation of the tyrosine kinases Fyn, Lck and ZAP-70 leading to selective disruption of TCR coupling to the phospholipase D, protein kinase C, phosphoinositide-3-kinase and RasMAPkinase signalling cascades. These cascades are key 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 suggest that PC-ES may play a role in the induction of T lymphocyte hyporesponsiveness observed during filarial infections.
Harnett
M M
MM
Department of Immunology, University of Glasgow, Scotland, UK.
Deehan
M R
MR
Williams
D M
DM
Harnett
W
W
D000595:Amino Acid Sequence; D000818:Animals; D017252:CD3 Complex / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D004153:Dipetalonema; D004789:Enzyme Activation / Q000187:drug effects; D015801:Helminth Proteins / Q000494:pharmacology*; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D008969:Molecular Sequence Data; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010739:Phospholipase D / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism