Engineering Th determinants for efficient priming of humoral and cytotoxic T cell responses.
To engineer T(h) determinants (THd) to prime help for humoral or cytotoxic T cell responses, we modified ovalbumin [OVA(323-337)] and myoglobin [MYO(106-118)] eliciting T(h)1 and T(h)0 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-gamma and IL-4 production. Peptides eliciting different proportions of IFN-gamma and IL-4 were co-immunized with a peptide hapten or a T cytotoxic determinant (TCd) respectively. OVA(323-337)- and MYO(106-118)-derived peptides afforded the best THd for the induction of cytotoxic T lymphocyte (CTL) and anti-hapten antibodies respectively. IFN-gamma and IL-4, primed by MYO(106-118)-derived peptides, correlated significantly with antibody production against the hapten (P < 0.05 for IFN-gamma and P < 0.05 for IL-4). Interestingly, two peptides derived from OVA(323-337), 323G and 327G, which induced the clearest T(h)2 cytokine profiles, were not the most efficient to prime cell help for the induction of anti-hapten antibodies. For CTL induction, OVA(323-337)-derived peptides, inducing a T(h)1-like profile, required a lower dose (5 nmol) than T(h)0 peptides (50 nmol). The dose of 50 nmol was detrimental for T(h)1-like peptides. Interestingly, IFN-gamma primed by the THd correlated significantly with that induced by the TCd (P < 0.01).
Universidad de Navarra, Division de Hepatología y Terapia Génica, Facultad de Medicina. Irunlarrea 1, 31008 Pamplona, Spain.
Ascensión
A
López-Díaz de Cerio
Juan José
JJ
Lasarte
Noelia
N
Casares
Pablo
P
Sarobe
Marta
M
Ruiz
Jesús
J
Prieto
Francisco
F
Borrás-Cuesta
D000818:Animals; D000906:Antibodies / Q000032:analysis; D017951:Antigen Presentation / Q000276:immunology*; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D006241:Haptens / Q000276:immunology*; D016898:Interferon-alpha / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D009211:Myoglobin / Q000737:chemistry / Q000276:immunology; D010047:Ovalbumin / Q000737:chemistry / Q000276:immunology; D010455:Peptides / Q000737:chemistry / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
D000906:Antibodies; D006241:Haptens; D016898:Interferon-alpha; D007376:Interleukin-2; D009211:Myoglobin; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D015847:Interleukin-4; D010047:Ovalbumin