Thymocyte and thymic epithelial cell (TEC) development are interdependent processes. Although lineage relationships among progressively maturing thymocyte subsets have been characterized, the developmental relationships among TEC subsets are obscure. Because epithelial cells express distinct keratin (K) species as a function of differentiation stage and proliferative status, we used K expression patterns to identify mouse TEC subsets and determine their lineage relationships. CD25ϩ pre-T cells that productively rearrange the TCR␤ locus and express pre-TCR͞CD3 complexes proliferate and differentiate to the CD4 ϩ CD8 ϩ double-positive (DP) stage. The DN to DP transition is accompanied by loss of CD25 expression, prohibition of TCR␤ locus rearrangements, and induction of TCR␣ locus rearrangements. Signaling through the ␣␤TCR͞CD3 complexes on DP thymocytes mediates the positive and negative selection processes that shape the T-cell repertoire. DP thymocytes that are positively selected by self-peptide͞major histocompatibility complex molecules presented on cortical epithelial cells terminate CD8 or CD4 expression and migrate to the thymic medulla.Thymic epithelial cells (TECs) are not only involved in the selection of DP cells, but also promote differentiation of early DN thymocyte precursors. Nude mice that are unable to generate a normal thymic epithelial compartment because of an inactivating whn gene mutation have a primitive thymic anlage devoid of T cells (3). Furthermore, recent studies have shown that the maturation of DN precursors in thymic organ culture requires the presence of major histocompatibility complex class II ϩ TECs (4-6). Although TECs are known to play a critical role in T-cell maturation, the factors that govern TEC development are incompletely understood, particularly in comparison to the well-characterized T-cell developmental process. Nevertheless, it is clear that the establishment of normal thymic architecture and thus, TEC differentiation, depends on thymocyte͞TEC interactions (7,8). This interdependence is apparent in mice that express a human CD3 (hCD3) transgene, which prevents T-cell maturation beyond the primitive CD44 ϩ CD25 Ϫ

We previously reported that precursors within the keratin (K) 8+5+ thymic epithelial cell (TEC) subset generate the major cortical K8+5− TEC population in a process dependent on T lineage commitment. This report demonstrates that expression of a cyclin D1 transgene in K8+5+ TECs expands this subset and promotes TEC and thymocyte development. Cyclin D1 transgene expression is not sufficient to induce TEC differentiation in the absence of T lineage-committed thymocytes because TECs from both hCD3ε transgenic and hCD3ε/cyclin D1 double transgenic mice remain blocked at the K8+5+ maturation stage. However, enforced cyclin D1 expression does expand the developmental window during which K8+5+ cells can differentiate in response to normal hemopoietic precursors. Thus, enhancement of thymic function may be achieved by manipulating the growth and/or survival of TEC precursors within the K8+5+ subset.

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