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Negative selection during the peripheral immune response to antigen.

S M Anderton1, C G Radu, P A Lowrey

  • 1Department of Pathology and Microbiology, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, United Kingdom. steve.anderton@ed.ac.uk

The Journal of Experimental Medicine
|January 4, 2001
PubMed
Summary

Peripheral T cell expansion is controlled by T cell receptor avidity. High-affinity T cells are eliminated by apoptosis when exposed to strong antigens, preventing autoimmune disease and informing vaccine design.

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Area of Science:

  • Immunology
  • T cell biology
  • Autoimmunity

Background:

  • Thymic selection relies on T cell avidity for antigen-MHC complexes.
  • Peripheral mechanisms for T cell repertoire expansion are not well understood.

Purpose of the Study:

  • To investigate an avidity-based model for peripheral T cell clonal expansion.
  • To understand how antigen strength influences T cell responses and disease development.

Main Methods:

  • Used an encephalitogenic peptide epitope from myelin basic protein (Ac1-9) as a model antigen.
  • Generated peptide analogues with varying binding affinities to the H-2 A(u) molecule.
  • Assessed T cell repertoire expansion and antigen sensitivity in vivo after immunization.

Main Results:

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  • Immunization with weak antigens expanded high-affinity T cells, inducing experimental autoimmune encephalomyelitis.
  • Stronger antigenic analogues induced apoptosis of high-affinity T cells, preventing disease.
  • The T cell repertoire consistently tuned to a specific activation threshold for the immunizing antigen.

Conclusions:

  • Peripheral T cell expansion is regulated by antigen avidity, with high avidity leading to tolerance.
  • This avidity-based tuning mechanism controls autoreactive T cell expansion.
  • Findings have implications for immunotherapy and vaccine development strategies.