A filarial cysteine protease inhibitor down‐regulates T cell proliferation and enhances interleukin‐10 production

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Abstract
Filarial nematodes are a cause of chronic debilitating diseases in the tropics. A hallmark of filariasis is the marked down‐regulation and polarization of host immune responses, yet molecular constituents of parasites causing this state have remained undefined. We describe a 17‐kDa antigen (Av17) of the rodent filarial parasite Acanthocheilonema viteae, which shows amino acid homologies to cystatin C, a major cysteine protease inhibitor belonging to family 2 of the cystatin superfamily. Av17 is released by filariae in vitro. Exported molecules of A. viteae worms are shown to markedly suppress mitogen‐induced T cell proliferation of mice and jirds. Av17 accounts for 45.5% of this suppressive activity in the murine system. Recombinant Av17 (rAv17), expressed in Escherichia coli, exhibits biological activity as a cysteine protease inhibitor and was used to examine the immunomodulatory effects. rAv17 induces down‐regulation of murine T cell responses to mitogens, to T cell receptor cross‐linking by anti‐CD3 antibodies and to specific antigens, and at the same time up‐regulation of interleukin‐10. Hence, this filarial cystatin is a likely effector molecule of immunomodulation and a potential target for antifilarial intervention.