The affinity threshold for antigenic triggering differs for tolerance susceptible immature precursors vs mature primary B cells

Abstract

The specificity of antibody responses is dependent on the extent to which a given antigen selectively stimulates cells from within a diverse B cell repertoire. Previous studies have shown that the triggering of B cells by T cell-dependent antigens is a highly discriminatory process, and that tolerance induction of immature B cells by antigen is equally discriminatory. This symmetry in the requirements for stimulation and tolerance induction could provide a basis for the capacity of antibody responses to discriminate among foreign antigens and yet minimize self recognition. The extent to which this potential for discriminate recognition is applicable to the mature immune system remains controversial, because B cells reactive to self antigens have been identified and, in addition, several investigators have identified heteroclitic immune responses, such as the response to NP of Ighb mice, wherein antibodies are found with higher affinities for analogues of the immunogen than for the immunogen itself. To further investigate the capacity of B cells to discriminate among closely related antigenic determinants, we analyzed the fine specificity and idiotypic distribution of monoclonal antibodies derived from both splenic B cells and immature sIg- bone marrow B cell precursors stimulated in fragment culture with NP-Hy and its structural analogues NIP-Hy and NNP-Hy. The results indicate that the majority of responsive B cells discriminate among these haptenic determinants; however, lambda-bearing B cells responsive to the NP and NIP determinants represent a highly overlapping set of clonotypes. Comparison of the responses to NP-Hy and NIP-Hy of splenic vs sIg- precursors of this clonotype family suggests that the T cell-dependent stimulation of both mature and immature B cells by antigen is highly affinity dependent. Significantly, the affinity thresholds for both stimulation and tolerance induction of immature B cells appears to be higher than that required for the stimulation of mature splenic B cells. Such a disparity in the requisites for triggering mature vs immature B cells could readily account for the presence of low-affinity self-reactive B cells in the mature B cell pools of normal individuals.