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Thymic selection depends on positive and negative selective mechanisms based on the avidity of T cell interaction with antigen–major histocompatibility complex complexes. However, peripheral mechanisms for the recruitment and 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 encephalitogenic, H-2 A u -restricted, acetylated NH 2 -terminal nonameric peptide (Ac1-9) epitope from myelin basic protein as our model antigen. Peptide analogues 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, these analogues elicited distinct repertoires of T cells that displayed marked differences in antigen sensitivity. Immunization with the weakest (wild-type) antigen expanded the high affinity T cells required to induce encephalomyelitis. In contrast, immunization with strongly antigenic analogues led to the elimination of T cells bearing high affinity T cell receptors by apoptosis, thereby preventing disease development. Moreover, the T cell repertoire was consistently tuned to respond to the immunizing antigen with the same activation threshold. This tuning mechanism provides a peripheral control against the expansion of autoreactive T cells and has implications for immunotherapy and vaccine design. T cells repertoire selection autoimmunity encephalomyelitis apoptosis Footnotes Abbreviations used in this paper: 7-AAD, 7-amino actinomycin D; CFSE, carboxyfluorescein diacetate succinimidyl ester; EAE, experimental autoimmune encephalomyelitis; MBP, myelin basic protein; PLNC, primed lymph node cell; TCL, T cell line. Submitted: 5 July 2000 Revision requested 19 October 2000 Accepted: 30 October 2000
The Journal of Experimental Medicine – Rockefeller University Press
Published: Jan 1, 2001
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