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Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, Epalinges, Switzerland
The involvement of a variety of clonal selection processes during
the development of T lymphocytes in the thymus has been well
established. Less information, however, is available on how homeostatic
mechanisms may regulate the generation and maturation of thymocytes. To
investigate this question, mixed radiation bone marrow chimeras were
established in which wild-type T cell precursors capable of full
maturation were diluted with precursors deficient in maturation
potential because of targeted mutations of the RAG1 or
TCR-
genes. In chimeras in which the majority of
thymocytes are blocked at the
CD4-CD8-CD25+ stage (RAG1
deficient), and only a small proportion of T cell precursors are of
wild-type origin, we observed no difference in the maturation of
wild-type CD4-CD8-CD25+ cells to
the CD4+CD8+ stage as compared with control
chimeras. Therefore, the number of cell divisions occurring during this
transition is fixed and not subject to homeostatic regulation. In
contrast, in mixed chimeras in which the majority of thymocytes are
blocked at the CD4+CD8+ stage (TCR-
deficient), an increased efficiency of development of wild-type mature
CD8+ cells was observed. Surprisingly, the rate of
generation of mature CD4+ thymocytes was not affected in
these chimeras. Thus, the number of selectable CD8 lineage thymocytes
apparently saturates the selection mechanism in normal mice while the
development of CD4 lineage cells seems to be limited only by the
expression of a suitable TCR. These data may open the way to the
identification of homeostatic mechanisms regulating thymic output and
CD4/CD8 lineage commitment, and the development of means to modulate
it.
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