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T cell-stimulatory Fragments of Foot-and-mouth Disease Virus Released by Mild Treatment With Cathepsin D

¹ Department of Immunology, Institute of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, University of Utrecht, P.O. Box 80. 165, 3508 TD Utrecht,
² TNO Medical Biological Laboratory, P.O. Box 5815, 2280 HV, Rijswijk
and³ Institute of Animal Science and Health, ID-DLO, P.O. Box 65, 8200 AB, Lelystad, The Netherlands

Cathepsin D and cathepsin B are endosomal/lysosomal proteases that are thought to play a role during in vivo antigen processing, releasing fragments for binding to major histocompatibility complex class II products and subsequent presentation to T cells. Here we treated purified foot-and-mouth disease virus (FMDV) strain A₁₀Holland with both enzymes. Cathepsin D, but not cathepsin B, was shown to release fragments from reduced or non-reduced FMDV under mild conditions in vitro. Twenty-eight predominant cathepsin D-released fragments were purified by HPLC and identified by amino acid composition analysis and sequencing. The unseparated set of fragments produced (the digest) was able to stimulate T cells from eight vaccinated cattle. With respect to the response to intact virus the extent of the response to the digest differed between animals: four animals could be classified as good responders, three as intermediate responders and one as a low responder. Subsequently, we investigated the proliferative T cell response to a large set of synthetic peptides in detail for two animals, one belonging to the group of good responders, the other being the low responder. The peptides covered all 28 cathepsin D-released fragments analysed and also several sequences not recovered from the digest. In this way seven T cell sites could be identified, five of which coincided with cathepsin D-released fragments. The other two T cell sites were VP2[54–72], being a homologue of a T cell site identified for FMDV strain O₁K and the N terminus of VP4. Whether the most dominantly recognized T cell site was recovered from the digest or not was shown to be related to the good or low response to the digest. These findings suggest a role for cathepsin D in the release of some but not all T cell-stimulatory fragments from FMDV.

Received 17 December 1993; accepted 10 June 1994.