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MHC Class I-Restricted Cytotoxic Lymphocyte Responses Induced by Enterotoxin-Based Mucosal Adjuvants¹

Cameron P. Simmons^2,*, Pietro Mastroeni^*, Ray Fowler^*, Marjan Ghaem-maghami^*, Nils Lycke, Mariagrazia Pizza, Rino Rappuoli and Gordon Dougan^*

^* Department of Biochemistry, Imperial College of Science, Technology and Medicine, South Kensington, London, United Kingdom; The Chiron Vaccines Immunological Research Institute, Via Fiorentina, Siena, Italy; and Department of Medical Microbiology and Immunology, University of Goteborg, Goteborg, Sweden

The ability of enterotoxin-based mucosal adjuvants to induce CD8⁺ MHC class I-restricted CTL responses to a codelivered bystander Ag was examined. Escherichia coli heat-labile toxin (LT), or derivatives of LT carrying mutations in the A subunit (LTR72, LTK63), were tested in parallel with cholera toxin (CT) or a fusion protein consisting of the A1 subunit of CT fused to the Ig binding domain of Staphylococcus aureus protein A (called CTA1-DD). Intranasal (i.n.) immunization of C57BL/6 mice with CT, CTA1-DD, LT, LTR72, LTK63, but not rLT-B, elicited MHC class I-restricted CD8⁺ T cell responses to coadministered OVA or the OVA CTL peptide SIINFEKL (OVA_257–264). CT, LT, and LTR72 also induced CTL responses to OVA after s.c. or oral coimmunization whereas LTK63 only activated responses after s.c. coimmunization. rLT-B was unable to adjuvant CTL responses to OVA or OVA_257–264 administered by any route. Mice treated with an anti-CD4 mAb to deplete CD4⁺ T cells mounted significant OVA-specific CTL responses after i.n. coadministration of LT with OVA or OVA_257–264. Both ⁵¹Cr release assays and IFN- enzyme-linked immunospot assays indicated that IFN-^-/- and IL-12 p40^-/- gene knockout mice developed CTL responses equivalent to those detected in normal C57BL/6 mice. The results highlight the versatility of toxin-based adjuvants and suggest that LT potentiates CTL responses independently of IL-12 and IFN- and probably by a mechanism unrelated to cross-priming.

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