Early Growth Response Gene 1 Provides Negative Feedback to Inhibit Entry of Progenitor Cells into the Thymus

Abstract

The size of the thymus can be greatly influenced by changes in the small number of early progenitors in the thymus. However, it is not known whether thymic cellularity feeds back to regulate the recruitment, survival, and expansion of progenitors. The transcription factor early growth response gene 1 (Egr1) has been implicated in controlling proliferation and survival in many cell types. We have previously shown that mice deficient in Egr1 have increased thymic cellularity. We now show that Egr1 regulates a negative feedback signal that controls the entry of cells into the thymus. Egr1-deficient mice have higher percentages of early T lineage progenitors in the thymus, yet Egr1-deficient mice have normal numbers of myelolymphoid progenitors in the bone marrow, and Egr1-deficient thymocytes show normal rates of apoptosis and proliferation at all stages of development. Evidence from mixed bone marrow chimeras shows that the ability of Egr1 to control progenitor recruitment is mediated by bone marrow-derived cells, but is not cell autonomous. Furthermore, Egr1-deficient thymuses have increased P-selectin expression. The data suggest that Egr1 mediates a feedback mechanism whereby the number of resident double negative thymocytes controls the entry of new progenitors into the thymus by regulating P-selectin expression on thymic endothelial cells.