title: Immature thymocytes employ distinct signaling pathways for allelic exclusion versus differentiation and expansion.
abstract: T cell receptor (TCR) beta chain allelic exclusion occurs at the thymocyte CD4- 8- (double-negative, or DN) to CD4+ 8+ (double-positive, or DP) transition, concurrently with differentiation and cellular expansion, and is imposed by a negative feedback loop in which a product of the first rearranged TCRbeta allele arrests further recombination in the TCRbeta locus. All of the major events associated with the development of DP cells can be induced by the introduction of TCRbeta or activated Lck transgenes. Here, we present evidence that the signaling pathways that promote thymocyte differentiation and expansion of RAG-deficient DN cells but not those that suppress rearrangements of endogenous TCRbeta genes in normal DN cells are engaged by activated Ras. We propose that TCRbeta allelic exclusion is mediated by effector pathways downstream of Lck but independent of Ras.
authors.affiliation: Howard Hughes Medical Institute, The Children's Hospital, and The Center for Blood Research, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: F
authors.initials: F
authors.lastname: Gärtner
authors.forename: F W
authors.initials: FW
authors.lastname: Alt
authors.forename: R
authors.initials: R
authors.lastname: Monroe
authors.forename: M
authors.initials: M
authors.lastname: Chu
authors.forename: B P
authors.initials: BP
authors.lastname: Sleckman
authors.forename: L
authors.initials: L
authors.lastname: Davidson
authors.forename: W
authors.initials: W
authors.lastname: Swat
mesh_terms: D000483:Alleles; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D002454:Cell Differentiation / Q000235:genetics; D002455:Cell Division / Q000235:genetics; D015870:Gene Expression; D015321:Gene Rearrangement; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000235:genetics; D051379:Mice; D009154:Mutation; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D013601:T-Lymphocytes / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology*; D019076:Transgenes / Q000235:genetics; D018631:ras Proteins / Q000235:genetics
chemical_list: D016693:Receptors, Antigen, T-Cell, alpha-beta; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D018631:ras Proteins