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Original Article

^a Department of Pathology and Microbiology, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, United Kingdom
^b Cancer Immunobiology Center, University of Texas Southwestern Medical Center, Dallas, Texas 75235
Institute of Cell, Animal and Population Biology, University of Edinburgh, Ashworth Laboratories, King's Buildings, West Mains Rd., Edinburgh EH9 3JT, UK.44-131-650 732244-131-650 5499

steve.anderton{at}ed.ac.uk

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 NH₂-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.

Key Words: T cells • repertoire selection • autoimmunity • encephalomyelitis • apoptosis

© 2001 The Rockefeller University Press

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