THE ROLES OF ANTIBODY VARIABLE REGION HYPERMUTATION AND SELECTION IN THE DEVELOPMENT OF THE MEMORY B-CELL COMPARTMENT

Somatic hypermutation and selection of immunoglobulin (Ig) variable (V )-region genes, working in concert, appear to be essential for memory B-cell development in mammals. There has been substantial progress on the nature of the cis-acting DNA elements that regulate hypermutation. The data obtained suggest that the mechanisms of Ig gene hypermutatio n and transcription are intimately intertwined. While it has long been appreciated that stringent phenotypic selection forces are imposed on the somatically mutated Ig V regions generated during a T-cell depend ent B-cell response, the mechanisms involved in this selection have re mained enigmatic. Our studies have questioned the role of foreign anti gen deposited on follicular dendritic cells in affinity-based positive selection of V regions, and have shown that this selection takes plac e in a ''clone-autonomous'' fashion. In addition, our data strongly su ggest that affinity for antigen alone is nor the driving force for sel ection of B-cell clones into the memory compartment. In contrast, we s uggest that a combination of positive selection for increased foreign antigen binding, and negative selection of antibody V regions that are autoreactive at the onset of the response, or have acquired autoreact ivity via hypermutation, results in the ''specificity maturation'' of the memory B-cell response.