Insertional mutagenesis affecting programmed cell death leads to thymic hyperplasia and altered thymopoiesis.
The mouse mutant Ft displays thymic hyperplasia and fused toes (Ft) of the forelimbs. Both phenotypic abnormalities are caused by transgene insertion in the D region of chromosome 8. While the forelimb defect is probably caused by developmentally dysregulated programmed cell death, the mechanism underlying thymic hyperplasia has not been characterized. In this work, we show that expansion of the thymocyte compartment progresses with time, is polyclonal, and affects all major thymocyte subsets, including the earliest CD4-8- subset, i.e., CD44+ CD25- cells; hyperplasia is not an autonomous property of mutant T cells, but is caused indirectly by a primary defect in thymic stromal. The rate of cell division and the cell turnover of immature CD4-8- and CD4+8+ thymocytes under steady state conditions are not altered in hyperplastic Ft thymi. Immature CD4+8+ thymocytes of mutant mice, however, are less susceptible to induction in vitro of programmed cell death by different modes (TCR cross-linking, cortisone, or radiation). Increased production of thymocytes results in increased export of T cells, yet the size and composition of the peripheral T cell pool are normal. Overproduction of immature CD4+8+ thymocytes is offset partly by a reduced conversion rate of CD4+8+ double positive to single positive thymocyte growth control by epithelial cells, and may serve as a model to study the regulation of early thymopoiesis.
Volkmann
A
A
Division of Cellular Immunology, German Cancer Research Center, Heidelberg, Germany.
Döffinger
R
R
Rüther
U
U
Kyewski
B A
BA
D000818:Animals; D017209:Apoptosis / Q000235:genetics* / Q000276:immunology; D002453:Cell Cycle / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D006411:Hematopoiesis, Extramedullary / Q000276:immunology* / Q000528:radiation effects; D006706:Homeostasis / Q000276:immunology; D006965:Hyperplasia; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D016513:Mice, SCID; D016254:Mutagenesis, Insertional / Q000276:immunology*; D011828:Radiation Chimera; D017154:Stromal Cells / Q000473:pathology / Q000528:radiation effects; D013601:T-Lymphocytes / Q000473:pathology; D013950:Thymus Gland / Q000276:immunology / Q000473:pathology* / Q000528:radiation effects