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

Regulatory mechanisms involved in the induction and progression of T-depend ent humoral responses have been extensively delineated using a variety of h aptens 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 pe ptides 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 repert oire and epitope, fine specificities of early activated clonotypes. Selecti on at this stage is on the basis of affinity for epitope, which, in turn, i s under thermodynamic control. This selected B-cell subset proceeds to popu late germinal centers, where further optimization - by way of somatic hyper mutation followed by clonal selection - is in favor of increased on-rates o f antigen binding. Thus, contrary to findings with hapten antigens, maturat ion of antibody responses to polypeptides occurs in two discrete, but seque ntial, stages. The first is for B cells with optimum affinity for the corre sponding epitope. This is then followed by further improvement on the basis of increased on-rates of antigen/epitope binding. It is a combination of t hese two processes which results in the high fidelity of antibodies produce d in the secondary response.