Engineering Th determinants for efficient priming of humoral and cytotoxic T cell responses

Abstract

To engineer Th determinants (THd) to prime help for humoral or cytotoxic T cell responses, we modified ovalbumin [OVA323-337] and myoglobin [MYO106-118] eliciting Th1 and Th0 cytokine profiles respectively. Residues along the sequence of both THd were replaced with amino acids representative of different families. Replacements at positions P-1 and P5 pointing to the TCR in both THd afforded higher levels of IFN-γ and IL-4 production. Peptides eliciting different proportions of IFN-γ and IL-4 were co-immunized with a peptide hapten or a T cytotoxic determinant (TCd) respectively. OVA323-337- and MYO106-118-derived peptides afforded the best THd for the induction of cytotoxic T lymphocyte (CTL) and anti-hapten antibodies respectively. IFN-γ and IL-4, primed by MYO106-118-derived peptides, correlated significantly with antibody production against the hapten (P < 0.05 for IFN-γ and P < 0.05 for IL-4). Interestingly, two peptides derived from OVA323-337, 323G and 327G, which induced the clearest Th2 cytokine profiles, were not the most efficient to prime cell help for the induction of anti-hapten antibodies. For CTL induction, OVA323-337-derived peptides, inducing a Th1-like profile, required a lower dose (5 nmol) than Th0 peptides (50 nmol). The dose of 50 nmol was detrimental for Th1-like peptides. Interestingly, IFN-γ primed by the THd correlated significantly with that induced by the TCd (P < 0.01).