Onset of TCR-beta gene rearrangement and role of TCR-beta expression during CD3-CD4-CD8- thymocyte differentiation.
TCR-beta gene rearrangement or expression is necessary and sufficient for the progression of early alpha beta thymocyte differentiation from the CD3-CD4-CD8- triple negative (TN)3 to the CD4+CD8+ double positive stage. The onset of TCR-beta rearrangement is currently thought to occur gradually. Some thymocytes were reported to be rearranged at the earliest (CD44+CD25-) TN stage, whereas other thymocytes did not initiate TCR-beta rearrangement until the latest (CD44-CD25-) TN stage. Here, we have isolated subsets of TN thymocytes on the basis of surface expression of CD44 and CD25, with c-kit as an additional marker. We present a revised model of early T cell development in which TCR-beta and TCR-gamma rearrangements occur abruptly, at the CD44lowCD25+ c-kitlowTN stage. A high level of c-kit expression defines pro-T cells which have not yet rearranged their TCR genes. Germ-line TCR-beta transcripts, and transcripts of recombination activating genes (RAG)-1 and 2, are detected before TCR-beta gene rearrangement. Analyses of TN thymocytes of RAG-1 mutant mice, and of various TCR mutant and TCR transgenic RAG-1 mutant mice, indicate the existence of a control point at the CD44-CD25+TN stage at which cells expressing a productively rearranged TCR-beta chain are selected for further differentiation.
Godfrey
D I
DI
DNAX Research Institute, Palo Alto, CA 94304.
Kennedy
J
J
Mombaerts
P
P
Tonegawa
S
S
Zlotnik
A
A
D000818:Animals; D001483:Base Sequence; D017252:CD3 Complex / Q000032:analysis; D015704:CD4 Antigens / Q000032:analysis; D016827:CD8 Antigens / Q000032:analysis; D002352:Carrier Proteins / Q000032:analysis; D004268:DNA-Binding Proteins; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; D018398:Homeodomain Proteins; D018960:Hyaluronan Receptors; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D011506:Proteins / Q000032:analysis; D011518:Proto-Oncogene Proteins / Q000032:analysis; D019009:Proto-Oncogene Proteins c-kit; D020794:Receptor Protein-Tyrosine Kinases / Q000032:analysis; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000502:physiology*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000032:analysis; D011956:Receptors, Cell Surface / Q000032:analysis; D016184:Receptors, Colony-Stimulating Factor / Q000032:analysis; D016201:Receptors, Lymphocyte Homing / Q000032:analysis; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000502:physiology*
D017252:CD3 Complex; D015704:CD4 Antigens; D016827:CD8 Antigens; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D018960:Hyaluronan Receptors; D011506:Proteins; D011518:Proto-Oncogene Proteins; C499308:Rag2 protein, mouse; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016692:Receptors, Antigen, T-Cell, gamma-delta; D011956:Receptors, Cell Surface; D016184:Receptors, Colony-Stimulating Factor; D016201:Receptors, Lymphocyte Homing; C064655:V(D)J recombination activating protein 2; C064658:RAG-1 protein; D019009:Proto-Oncogene Proteins c-kit; D020794:Receptor Protein-Tyrosine Kinases