Negative selection during the peripheral immune response to antigen

Thymic selection depends oil positive and negative selective mechanisms bas ed on the avidity of T cell interaction with antigen-major histocompatibili ty complex complexes. However, peripheral mechanisms for the recruitment an d clonal expansion of the responding T cell repertoire remain obscure. Here we provide evidence for an avidity-based model of peripheral T cell clonal expansion in response to antigenic challenge. We have used the encephalito genic, H-2 A(u)-restricted, acetylated NH2-tenuinal nonameric peptide (Acl- 9) epitope from myelin basic protein as our model antigen. Peptide analogue s were generated that varied in antigenic strength (as assessed by in vitro assay) based on differences in their binding affinity for A(u). In vivo, t hese analogues elicited distinct repertoires of T cells that displayed mark ed differences in antigen sensitivity. Immunization with the weakest (wild- type) antigen expanded the high affinity T cells required to induce encepha lomyelitis. In contrast, immunization with strongly antigenic analogues led to the elimination of T cells bearing high affinity T cell receptors by ap optosis, thereby preventing disease development. Moreover, the T cell reper toire was consistently tuned to respond to the immunizing antigen with the same activation threshold. This tuning mechanism provides a peripheral cont rol against the expansion of autoreactive T cells and has implications for immunotherapy and vaccine design.