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How many thymocytes audition for selection?

M Merkenschlager1, D Graf, M Lovatt

  • 1Lymphocyte Development Group, Medical Research Council Clinical Sciences Centre, Royal Postgraduate Medical School, Hammersmith Hospital, London W12 0NN, United Kingdom. mmerkens@rpms.ac.uk

The Journal of Experimental Medicine
|October 7, 1997
PubMed
Summary
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Most thymocytes that respond to major histocompatibility complex (MHC) ligands fail to mature. This study reveals that many MHC-reactive thymocytes are eliminated during T cell selection, explaining the low maturation rate.

Area of Science:

  • Immunology
  • Cell Biology
  • Developmental Biology

Background:

  • T cell maturation in the thymus involves T cell receptor (TCR) rearrangement and selection based on interactions with major histocompatibility complex (MHC) ligands.
  • A very small fraction (3-5%) of thymocytes successfully mature into the peripheral T cell pool, indicating a highly stringent selection process.

Purpose of the Study:

  • To investigate the frequency of pre-selection thymocytes capable of responding to MHC ligands.
  • To understand the basis for the low success rate of T cell maturation during thymic selection.

Main Methods:

  • Measurement of MHC-reactive thymocyte frequency using activation marker upregulation.
  • Short-term reaggregate culture of thymocytes with MHC-expressing thymic stroma.
  • Analysis of TCR transgenic thymocytes exposed to various MHC-peptide complexes.

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Main Results:

  • Up to 20% of MHC-naive thymocytes exhibited activation marker upregulation upon exposure to MHC-expressing thymic stroma.
  • The majority of these activated thymocytes showed physiological changes indicative of entering the selection process within 24 hours.
  • CD69 induction was identified as a reliable indicator of thymocyte selection (both positive and negative).

Conclusions:

  • The proportion of thymocytes capable of initiating the selection process significantly exceeds the number that successfully complete it.
  • A substantial number of MHC-reactive thymocytes are actively eliminated during positive and negative selection.
  • This high rate of elimination during selection accounts for the low overall T cell maturation yield.