c-Myc controls the development of CD8 TCR 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 CD8 T cells (expressing T-cell receptor [TCR ]) and unconventional CD8 T cells (expressing either TCR or TCR ). Whereas conventional IELs are widely accepted to arise from recirculation of activated CD4 and CD8 T cells from the secondary lymphoid organs to the gut, the origin and developmental pathway of unconventional CD8 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 CD8 TCR IELs. In the absence of c-Myc, CD4 CD8 TCR thymic precursors of CD8 TCR IELs are present but fail to develop on adoptive transfer in immunoincompetent hosts. Residual cMyc–deficient CD8 TCR 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 CD8 TCR IEL in c-Myc–deficient mice. Taken together, our data support a model in which c-Myc controls the development of CD8 TCR IELs from thymic precursors by regulating interleukin-15 receptor expression and consequently Bcl-2–dependent survival. (Blood. 2010;115(22):4431-4438)