Epitope-specific regulation. II. A bistable, Igh-restricted regulatory mechanism central to immunologic memory

Abstract

Antibody responses to commonly used antigens are regulated by an epitope- specific system composed of Igh-restricted elements responsible for controlling the isotype and allotype responses mounted to each of the epitopes on the antigen. Because these elements can be independently induced to either suppress or support antibody production, this system as a whole provides an effector mechanism capable of selectively controlling the amount, affinity, isotype representation, and epitope-specificity of an antibody response. Sequential immunizations with a carrier molecule and a hapten conjugated to that carrier (carrier/hapten-carrier immunization) induce suppression for IgG responses to the hapten. IgG(2a), IgG(2b), and IgG(3) responses are easily suppressed, whereas IgG(1) responses tend to be more resistant. Once induced, suppression tends to be maintained; however, repeated stimulation with the hapten (on any carrier) eventually induces antibody production, first for IgG(1) and later for the more suppressible isotypes (IgG(2a), IgG(2b), IgG(3)). Antibody production, once initiated, also tends to be maintained. Ongoing IgG antihapten responses in animals primed with a hapten-carrier conjugate can be suppressed by subsequent carrier/hapten-carrier immunization (using a different carrier molecule); however, the suppression induced under these circumstances is substantially weaker, i.e., it mainly affects the more suppressible isotypes and is only strong enough to detect clearly in about one-half the immunized animals. Thus, the initiation of antibody production impairs the subsequent induction of suppression, and the initial induction of suppression tends to prevent subsequent initiation of antibody production. This reciprocal relationship defines a bistable regulatory mechanism, i.e., one that tends to maintain its initially induced state but is capable of shifting to the alternate state when stimulatory conditions so dictate. The operation of such a mechanism permits conditions surrounding the first immunization with an epitope (hapten) to strongly influence but not absolutely determine which and how many of the anti-epitope memory B cells generated by that immunization will subsequently be expressed. Thus, epitope- specific regulation, although subordinate to mechanisms that control memory B cell development (as opposed to expression), plays a key role in determining the magnitude, affinity, and isotype representation of anamnestic (memory) responses produced in response to previously encountered epitopes.