Selection in a T-dependent primary humoral response: new insights from polypeptide models.

Regulatory mechanisms involved in the induction and progression of T-dependent humoral responses have been extensively delineated using a variety of haptens as model antigens. However, several unanswered questions remain with respect to those elicited by structurally more complex molecules. Our own laboratory has been pursuing this latter aspect using designed synthetic peptides as model systems. The cumulative results indeed support that humoral responses to such antigens involve several additional layers of regulation, beyond that identified with haptens. At the first level, the multiplicity of antigenic determinants recognized by the preimmune B-cell pool is soon subject to competitive pressures that restrict, both at the level of repertoire and epitope, fine specificities of early activated clonotypes. Selection at this stage is on the basis of affinity for epitope, which, in turn, is under thermodynamic control. This selected B-cell subset proceeds to populate germinal centers, where further optimization--by way of somatic hypermutation followed by clonal selection--is in favor of increased on-rates of antigen binding. Thus, contrary to findings with hapten antigens, maturation of antibody responses to polypeptides occurs in two discrete, but sequential, stages. The first is for B cells with optimum affinity for the corresponding epitope. This is then followed by further improvement on the basis of increased on-rates of antigen/epitope binding. It is a combination of these two processes which results in the high fidelity of antibodies produced in the secondary response.