Epitope-specific regulation. I. Carrier-specific induction of suppression for IgG anti-hapten antibody responses.

The epitope-specific regulatory system selectively controls IgG antibody production to the individual (haptenic) determinants on a complex antigen. This system can be specifically induced to suppress primary and secondary IgG antibody responses to dinitrophenyl hapten (DNP) without interfering with antibody responses to epitopes on the carrier molecule on which the DNP is presented. Furthermore, once induced, it will specifically suppress responses to DNP presented on unrelated carrier molecules. Results summarized here obtained using widely different immunization conditions, and a variety of haptens and carrier molecules indicate that this regulatory system controls antibody production in most T-dependent antibody responses. Carrier-specific suppressor T cells (CTs) that arise shortly after priming with a carrier molecule such as keyhole limpet hemocyaninin (KLH) induce the epitope-specific system to suppress in situ and adoptive antibody responses to epitopes (e.g., DNP) presented subsequently on the priming carrier. These well-known regulatory T cells are commonly believed to regulate antibody production by interfering with carrier-specific help; however, by repeating the original CTs transfer experiments with additional controls that define the specificity of the mechanism mediating suppression in CTs recipients, we show that KLH-specific CTs regulate responses by inducing typical isotope- specific suppression for anti-DNP responses when the recipients are immunized with DNP-KLH. Thus, whether KLH-primed animals are immunized directly with DNP-KLH (KLH/DNP-KLH immunization sequence) or whether T cells from these animals are challenged with DNP-KLH in (nonirradiated)recipients, anti-DNP responses are persistently suppressed while anti-carrier responses proceed normally. The aqueous KLH-priming protocols usually used to generate CTs are marginally more effective in priming for in situ suppression-induction than the alum KLH-priming protocols commonly used to generate KLH-specific helper T cells and used here in KLH/DNP-KLH immunizations. Thus, studies presented show that priming with an antigenic (carrier) molecule simultaneously prepares the animal for the production of typical secondary (anamnestic) antibody responses to epitopes on the priming antigen and for the induction of epitope-specific suppression for antibody production to determinants presented subsequently on the same antigenic molecule. We discuss the mechanism(s) responsible for this duality and its significance for antibody responses in an accompanying publication that describes the bistable regulatory capabilities of the epitope-specific system.