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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 (OVA257-264). 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 OVA257-264 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 OVA257-264. Both 51Cr release assays and IFN-gamma enzyme-linked immunospot assays indicated that IFN-gamma-/- 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-gamma and probably by a mechanism unrelated to cross-priming.

Type

Journal

Journal of immunology (Baltimore, Md. : 1950)

Publication Date

12/1999

Volume

163

Pages

6502 - 6510

Addresses

Department of Biochemistry, Imperial College of Science, Technology and Medicine, South Kensington, London, United Kingdom. c.simmons@ic.ac.uk

Keywords

Nasal Mucosa, T-Lymphocytes, Helper-Inducer, T-Lymphocytes, Cytotoxic, Tumor Cells, Cultured, Animals, Mice, Inbred C57BL, Mice, Knockout, Mice, Cholera Toxin, Adenosine Diphosphate Ribose, Arginine, Lysine, Ovalbumin, Escherichia coli Proteins, Recombinant Fusion Proteins, Interleukin-12, Bacterial Toxins, Enterotoxins, Adjuvants, Immunologic, Histocompatibility Antigens Class I, Epitopes, T-Lymphocyte, Administration, Intranasal, Administration, Oral, Injections, Subcutaneous, Amino Acid Substitution, Lymphocyte Activation, Cytotoxicity, Immunologic, Interferon-gamma