Article: article from journal or magazin.
c-Myc controls the development of CD8alphaalpha TCRalphabeta intestinal intraepithelial lymphocytes from thymic precursors by regulating IL-15-dependent survival.
The murine gut epithelium contains a large population of thymus-derived intraepithelial lymphocytes (IELs), including both conventional CD4(+) and CD8alphabeta(+) T cells (expressing T-cell receptor alphabeta [TCRalphabeta]) and unconventional CD8alphaalpha(+) T cells (expressing either TCRalphabeta or TCRgammadelta). Whereas conventional IELs are widely accepted to arise from recirculation of activated CD4(+) and CD8alphabeta(+) T cells from the secondary lymphoid organs to the gut, the origin and developmental pathway of unconventional CD8alphaalpha IELs remain controversial. We show here that CD4-Cre-mediated inactivation of c-Myc, a broadly expressed transcription factor with a wide range of biologic activities, selectively impairs the development of CD8alphaalpha TCRalphabeta IELs. In the absence of c-Myc, CD4(-) CD8(-) TCRalphabeta(+) thymic precursors of CD8alphaalpha TCRalphabeta IELs are present but fail to develop on adoptive transfer in immunoincompetent hosts. Residual c-Myc-deficient CD8alphaalpha TCRalphabeta IEL display reduced proliferation and increased apoptosis, which correlate with significantly decreased expression of interleukin-15 receptor subunits and lower levels of the antiapoptotic protein Bcl-2. Transgenic overexpression of human BCL-2 resulted in a pronounced rescue of CD8alphaalpha TCRalphabeta IEL in c-Myc-deficient mice. Taken together, our data support a model in which c-Myc controls the development of CD8alphaalpha TCRalphabeta IELs from thymic precursors by regulating interleukin-15 receptor expression and consequently Bcl-2-dependent survival.
Adoptive Transfer, Animals, Antigens, CD8/metabolism, Apoptosis, CD8-Positive T-Lymphocytes/classification, CD8-Positive T-Lymphocytes/cytology, Cell Differentiation, Cell Proliferation, Cell Survival, Humans, Interleukin-15/metabolism, Intestinal Mucosa/cytology, Intestinal Mucosa/immunology, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Proto-Oncogene Proteins c-bcl-2/genetics, Proto-Oncogene Proteins c-bcl-2/metabolism, Proto-Oncogene Proteins c-myc/genetics, Proto-Oncogene Proteins c-myc/metabolism, Receptors, Antigen, T-Cell, alpha-beta/metabolism, Receptors, Interleukin-15/metabolism, Recombinant Proteins/genetics, Recombinant Proteins/metabolism, Signal Transduction, T-Lymphocyte Subsets/classification, T-Lymphocyte Subsets/cytology
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