T cell differentiation and turnover in the mature thymus

In contrast to the peripheral lymphoid tissues, the vast majority of thymocytes turn over at a very rapid rate. Thymocyte differentiation begins with a population of stem cells which seed the thymus continuously from the bone marrow; these cells appear to be pluripotential but rapidly become committed to the T cell lineage.

The earliest stem cells in the thymus are characterized by a CD4'°8- CD44+ CD25" (IL-2R") pheno-type. These cells proliferate extensively and give rise to CD4"8 CD44+ CD25+ cells and then to CD4"8" CD44" CD25+ cells (Figure 2). During this transition, the cells cease to divide and then rearrange the TCR 3 gene and begin to upregulate both CD4 and CD 8 molecules. The TCR 3 chain associates with a non-polymorphic a chain (gp33, pre-TCRa) and this het-erodimer initiates a new wave of proliferation, perhaps by binding to a ligand on stromal cells. Proliferation is extensive at this stage and leads to the production of early CD4+8+ blast cells. Through rearrangement of polymorphic a chain genes, CD4+8+ blast cells rapidly express the typical a3 TCR on the cell surface but at a low level. Proliferation ceases soon after c*3 TCR expression and the cells accumulate as typical small cortical CD4+8+ «3 TCR'° cells; these cells are CD44" CD25". The majority of small CD4+8+ cells survive for only a brief period (3—4 days) and die in situ from apoptosis. Only a small proportion of these cells undergo positive selection (see below).

The mature «3 TCRhi CD4+8" and CD4"8+ cells in the medulla are the direct descendants of CD4+8+

cells and display a relatively slow turnover. For obscure reasons, these cells remain in the medulla for up to 1-2 weeks before being released to the extrathymic environment.

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