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Rapid Functional Exhaustion and Deletion of CTL following Immunization with Recombinant Adenovirus¹

Philippe Krebs^*,, Elke Scandella^*, Bernhard Odermatt and Burkhard Ludewig^2,*

^* Research Department, Kantonal Hospital St. Gallen, St. Gallen, Switzerland; and Institute of Experimental Immunology and Department of Pathology, University Hospital Zürich, Zürich, Switzerland

Replication-deficient adenoviruses (recombinant adenovirus (rec-AdV)) expressing different transgenes are widely used vectors for gene therapy and vaccination. In this study, we describe the tolerization of transgene-specific CTL following administration of -galactosidase (gal)-recombinant adenovirus (Ad-LacZ). Using MHC class I tetramers to track gal-specific CTL, we found that a significant expansion of gal-specific CTL was restricted to a very narrow dose range. Functional analysis revealed that adenovirus-induced gal-specific CTL produced only very low amounts of effector cytokines and were unable to exhibit cytolytic activity in a ⁵¹Cr release assay. Furthermore, Ad-LacZ vaccination failed to efficiently clear established gal-positive tumors. The impaired function of Ad-LacZ-induced CTL correlated with the presence of persisting gal Ag in the liver. A further increase in the peripheral Ag load by injection of Ad-LacZ into SM-LacZ transgenic mice which express gal as self-Ag exclusively in peripheral nonlymphoid organs, resulted in the physical deletion of gal-specific CTL. Our results indicate first that CTL deletion in the course of adenoviral vaccination is preceded by their functional impairment and second, that the outcome of rec-AdV vaccination depends critically on the Ag load in peripheral tissues.

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