Early TCR expression and aberrant T cell development in mice with endogenous prerearranged T cell receptor genes.
The factors that regulate the rate of production of T cells by the thymus remain incompletely defined. To test whether generation of functional T cell receptors limits the rate of thymic T cell export, we made use of a line of mice, LN3alphabeta, that have endogenously prerearranged TCR genes. The prerearranged TCR genes were expressed abnormally early in hemopoietic development, indicating that RAG-mediated recombination, rather than transcription factor expression, is the key determinant of the initiation of robust TCR transcription. Thymic T cell export rates were similar between wild-type (wt) and LN3alphabeta mice, indicating that T cell maturation rates in these mice are determined by factors other than TCR gene rearrangement. In competitive bone marrow chimeras, however, LN3alphabeta thymocytes were out-competed by wt cells and failed to develop beyond the double-negative 4 stage. Furthermore, wt progenitors transplanted intrathymically into LN3alphabeta mice proliferated excessively, suggesting that increased proliferative signals in the LN3alphabeta thymus compensate for faulty T cell development driven by early TCR expression.
Serwold
Thomas
T
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA. tserwold@stanford.edu
Hochedlinger
Konrad
K
Inlay
Matthew A
MA
Jaenisch
Rudolf
R
Weissman
Irving L
IL
D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D005434:Flow Cytometry; D015329:Gene Rearrangement, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D016654:Genes, RAG-1; D051379:Mice; D008817:Mice, Mutant Strains; D053652:Nuclear Transfer Techniques; D011948:Receptors, Antigen, T-Cell / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000254:growth & development* / Q000276:immunology
D011948:Receptors, Antigen, T-Cell