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Matthias Merkenschlager^*, Daniel Graf^*, Matthew Lovatt^*, Ursula Bommhardt, Rose Zamoyska, and Amanda G. Fisher^*

From the ^* Lymphocyte Development Group, Medical Research Council Clinical Sciences Centre, Royal Postgraduate Medical School, Hammersmith Hospital, London W12 0NN, United Kingdom; and Division of Molecular Immunology, National Institute of Medical Research, London, United Kingdom

T cell maturation requires the rearrangement of clonotypic T cell receptors (TCR) capable of interacting with major histocompatibility complex (MHC) ligands to initiate positive and negative selection. Only 3–5% of thymocytes mature to join the peripheral T cell pool. To investigate the basis for this low success rate, we have measured the frequency of preselection thymocytes capable of responding to MHC. As many as one in five MHC-naive thymocytes show upregulation of activation markers on exposure to MHC-expressing thymic stroma in short-term reaggregate culture. The majority of these cells display physiological changes consistent with entry into the selection process within 24 h. By exposing TCR transgenic thymocytes to a range of MHC–peptide complexes, we show that CD69 induction is indicative of thymocyte selection, positive or negative. Our data provide evidence that the fraction of thymocytes that qualify to enter the thymic selection process far exceeds the fraction that successfully complete it, and suggest that most MHC-reactive thymocytes are actively eliminated in the course of selection.

Drs. D. Mathis, C. Benoist, B. Koller, H. von Boehmer, D. Kioussis, E. Spanopoulou, M. Owen, E. Simpson, W. Heath, and F. Carbone are thanked for mice; Drs. R. Hilton, R. Lechler, and D. Gray for cells; Dr. R. Edwards for help with statistics; and Drs. P. Travers and S. Jameson for communicating results before publication.

¹ Abbreviations used in this paper: β2m, β2 microglobulin; °, deficient; DP, double positive; HPRT, hypoxanthine guanine phosphoribosyl transferase; mRNA, messenger RNA; rag, recombination-activating gene; RT, reverse transcriptase; SP, single positive; TdT, terminal deoxynucleotidyl transferase.

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