Intradermal Immunization with rAAV1 Vector Induces Robust Memory CD8+ T Cell Responses Independently of Transgene Expression in DCs

• Published in: Molecular therapy 2017-10, Vol.25 (10), p.2309-2322
• Main Authors: Ghenassia, Alexandre, Gross, David-Alexandre, Lorain, Stéphanie, Tros, Fabiola, Urbain, Dominique, Benkhelifa-Ziyyat, Sofia, Charbit, Alain, Davoust, Jean, Chappert, Pascal
• Format: Article
• Language: English
• Subjects: Animals; Antigen presentation; Antigens; CD4-Positive T-Lymphocytes - metabolism; CD8 antigen; CD8-Positive T-Lymphocytes - metabolism; Conflicts of interest; cross-presentation; CTL; Cytotoxicity; Dendritic cells; Dendritic Cells - metabolism; Dependovirus - genetics; Experiments; Expression vectors; Female; Flow Cytometry; Genetic Vectors - genetics; Immunization; Immunological memory; Life Sciences; Long term memory; Lymphocytes; Lymphocytes T; Major histocompatibility complex; Male; Memory cells; Mice; Mice, Inbred C57BL; Original; rAAV; Skin; Spleen; Transgenes; vaccination; Vaccines
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1016/j.ymthe.2017.06.019

Recombinant adeno-associated viral (rAAV) vectors exhibit interesting properties as vaccine carriers for their ability to induce long-lasting antibody responses. However, rAAV-based vaccines have been suggested to trigger functionally impaired long-term memory CD8+ T cell responses, in part due to poor dendritic cell (DC) transduction. Such results, albeit limited to intramuscular immunization, undermined the use of rAAV as vaccine vehicles against intracellular pathogens. We report here that intradermal immunization with a model rAAV2/1-based vaccine drives the development of bona fide long-term memory CD8+ T cell responses. The intradermal route of immunization and the presence of potent major histocompatibility complex (MHC) class II responses showed synergistic effects on the overall quantity and quality of systemic long-term effector memory transgene-specific CD8+ T cells being generated against the transgene. Of key interest, we found that the induction of memory cytotoxic T lymphocytes (CTLs) following intradermal immunization was solely dependent on the cross-presentation of skin-expressed transgene products, which appeared highly enhanced as compared to muscle-expressed transgene products. Overall our results highlight key tissue-specific differences in transgene presentation pathway requirements of importance for the design of rAAV-based T cell-inducing vaccines. There is a lasting question about the ability of rAAV to induce protective CD8+ T cell responses. Chappert and colleagues now show that changing the route of immunization might help, and in the process they highlight striking differences in the underlying transgene presentation pathways in play between skin and muscle.