How many thymocytes audition for selection?
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.
Merkenschlager
M
M
Lymphocyte Development Group, Medical Research Council Clinical Sciences Centre, Royal Postgraduate Medical School, Hammersmith Hospital, London W12 0NN, United Kingdom. mmerkens@rpms.ac.uk
Graf
D
D
Lovatt
M
M
Bommhardt
U
U
Zamoyska
R
R
Fisher
A G
AG
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000276:immunology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D017637:Clonal Deletion; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000276:immunology; D005786:Gene Expression Regulation; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000276:immunology / Q000378:metabolism; D018398:Homeodomain Proteins; D037181:Lectins, C-Type; D008213:Lymphocyte Activation; D008285:Major Histocompatibility Complex / Q000276:immunology*; D051379:Mice; D016133:Polymerase Chain Reaction; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D012641:Selection, Genetic; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D013950:Thymus Gland / Q000196:embryology / Q000276:immunology*; D000099192:CD69 Antigens
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D017931:DNA Primers; D004268:DNA-Binding Proteins; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D018398:Homeodomain Proteins; D037181:Lectins, C-Type; D011948:Receptors, Antigen, T-Cell; D000099192:CD69 Antigens; C499308:Rag2 protein, mouse; C064655:V(D)J recombination activating protein 2; C064658:RAG-1 protein