Brief Definitive Report INDUCTION OF TOLERANCE TO ONE DETERMINANT ON A SYNTHETIC PEPTIDE DOES NOT AFFECT THE RESPONSE TO A SECOND LINKED DETERMINANT Implications for the Mechanism of Neonatal Tolerance Induction

Neonatal T lymphocyte tolerance to proteins has been extensively studied, but the underlying mechanisms are still unknown (1-3). One hypothesis is that tolerance is due to the inactivation of T cells on contact with antigen at an early stage of development. Alternatively, tolerance may be the result of the stimulation of other T cells, which actively suppress subsequent responses. We have developed a novel experimental system using peptides to analyze the tolerant state at the level of individual peptide determinants, and to detect functional suppression. This approach makes use of the finding that different T cell subpopulations appear to recognize different determinants (4, 5) . Thus, Ts specific for a distinct determinant(s) on a protein molecule suppress the response of T cells specific for other regions of the molecule . Although the mechanism of this antigen-bridging suppression is poorly understood, the ability of Ts to act across an antigen bridge has been confirmed experimentally by the coupling of Ts-inducing determinants (SD) to those recognized by the responding T cells (6, 7) . Further, proliferative T cells (Tp) can be stimulated, despite the presence of Ts, by fragments of the whole protein that bear the Tp-inducing determinant but lack the Ts-inducing determinant (8) . Peptides lacking a suppressor determinant can be used as probes to reveal latent responses in tolerant mice, i .e ., responses not induced by challenge with the whole molecule . Previously (9), we showed that neonatal tolerance can be induced by small synthetic cytochrome c peptides . In that system, the specificity of tolerance matched that of the response to the peptide, providing evidence for direct clonal inactivation . In this report, we show that the induction of tolerance to one determinant on a 23-amino acid peptide does not affect the response to a second determinant on the same peptide, as would be predicted in a suppressor model. Furthermore, the congruence of minimal immunogenic and tolerogenic peptides is demonstrated .