Notch signaling in thymic progenitor cells is essential to initiate the T-cellspecific gene expression program and commitment to the T-cell lineage (Fig. 8.18). First, Notch signaling induces the expression of two transcription factors, T-cell factor-1 (TCF1) and GATA3, each of which is required for T-cell development. Together, TCF1 and GATA3 initiate expression of several T-lineage-specific genes, such as those encoding components of the CD3 complex, as well as Rag1, a gene required for T-cell receptor and B-cell receptor gene rearrangements (see Fig. 8.18). However, TCF1 and GATA3 are not sufficient to induce the entire program of T-cell-specific gene expression. A third transcription factor, Bcl11b, is required to induce T-lineage commitment by restricting progenitor cells from adopting alternative fates; this final phase of T-cell commitment is a necessary prerequisite for activating the complete T-cell gene expression program.
8-12 T-cell precursors proliferate extensively in the thymus, but most die there.
T-cell precursors arriving in the thymus from the bone marrow spend up to a week differentiating there before they enter a phase of intense proliferation. In a young adult mouse the thymus contains about 108 to 2 × 108 thymocytes. About 5 × 107 new cells are generated each day; however, only about 106 to 2 × 106 (roughly 2–4%) of these leave the thymus each day as mature T cells. Despite the disparity between the number of T cells generated in the thymus and the number leaving, the thymus does not continue to grow in size or cell number. This is because about 98% of the thymocytes that develop in the thymus also die in the thymus by apoptosis (see Section 1-14). Cells undergoing apoptosis are recognized and ingested by macrophages, and apoptotic bodies, which are the residual condensed chromatin of apoptotic cells, are seen inside macrophages throughout the thymic cortex (Fig. 8.19). This apparently
Fig. 8.17 The epithelial cells of the thymus form a network surrounding developing thymocytes. In this scanning electron micrograph of the thymus, the developing thymocytes (the spherical cells) occupy the interstices of an extensive network of epithelial cells. Photograph courtesy of W. van Ewijk.
Fig. 8.18 The stages of α:β T-cell development in the mouse thymus correlate with the program of gene rearrangement, and the expression of cell-surface proteins, signaling proteins, and transcription factors.