Thymic Epithelial Cell Differentiation Research Articles

Thymus organogenesis and molecular mechanisms of thymic epithelial cell differentiation

In the mature thymus, thymocyte maturation depends on interactions with different thymic epithelial subtypes in a three-dimensional thymic architecture. However, the molecular mechanisms that generate these epithelial subtypes are not well understood. Evidence is accumulating that during fetal thymus development, epithelial cells differentiate by successive interactions with differentiating thymocytes. This review presents fetal thymus development as a process of organogenesis, the main function of which is to promote thymic epithelial cell differentiation and the generation of a functional thymic microenvironment. In this model, endoderm-derived epithelial cells are the driving force in generating the thymic primordium, with hematopoietic cells providing later signals that organize and pattern the developing thymus.

Transgenic Expression of Cyclin D1 in Thymic Epithelial Precursors Promotes Epithelial and T Cell Development

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 hCD3epsilon transgenic and hCD3epsilon/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.

Measles virus infection induces terminal differentiation of human thymic epithelial cells.

Measles virus infection induces a profound immunosuppression that may lead to serious secondary infections and mortality. In this report, we show that the human cortical thymic epithelial cell line is highly susceptible to measles virus infection in vitro, resulting in infectious viral particle production and syncytium formation. Measles virus inhibits thymic epithelial cell growth and induces an arrest in the G0/G1 phases of the cell cycle. Moreover, we show that measles virus induces a progressive thymic epithelial cell differentiation process: attached measles virus-infected epithelial cells correspond to an intermediate state of differentiation while floating cells, recovered from cell culture supernatants, are fully differentiated. Measles virus-induced thymic epithelial cell differentiation is characterized by morphological and phenotypic changes. Measles virus-infected attached cells present fusiform and stellate shapes followed by a loss of cell-cell contacts and a shift from low- to high-molecular-weight keratin expression. Measles virus infection induces thymic epithelial cell apoptosis in terminally differentiated cells, revealed by the condensation and degradation of DNA in measles virus-infected floating thymic epithelial cells. Because thymic epithelial cells are required for the generation of immunocompetent T lymphocytes, our results suggest that measles virus-induced terminal differentiation of thymic epithelial cells may contribute to immunosuppression, particularly in children, in whom the thymic microenvironment is of critical importance for the development and maturation of a functional immune system.

Interdependence of cortical thymic epithelial cell differentiation and T-lineage commitment.

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. As expected, cortical and medullary TEC subsets express distinct K expression patterns in the normal thymus. However, we detected two distinct cortical TEC subsets, a major K8(+)K5(-) subset and a minor K8(+)K5(+) subset, which is highly represented at the cortico-medullary junction. Both cortical TEC subsets are also present in recombination activating gene 1 (RAG-1(-/-)) and TCRbetaxdelta-/- thymi in which T-cell development is blocked at the CD4(-)CD8(-)CD25(+)CD44(-) pre-T cell stage. In contrast, K8(+)K5(+) TECs predominate in the thymi of human CD3epsilon transgenic mice in which thymocyte development is blocked at an earlier CD4(-)CD8(-)CD25(-)CD44(+) stage. Transplantation of newborn human CD3epsilon transgenic thymi under the kidney capsule of RAG-1(-/-) mice results in the emergence of K8(+)K5(-) TECs concomitant with the appearance of CD25(+) thymocytes. Together, the data suggest that cortical TEC development proceeds from a K8(+)K5(+) precursor subset to a K8(+)K5(-) stage in a differentiation process concomitant with T-cell lineage commitment.

Epithelial cell heterogeneity in mammalian thymus: Monoclonal antibody to high molecular weight keratins exclusively binds to Hassall's corpuscles

Hassall's corpuscles represent a subset of medullary thymic epithelial cells whose origin and function within the thymus still remain largely unknown. The present study shows that Hassall's corpuscles can be defined by their intracellular content in specific keratin subunits. Two monoclonal anti-keratin antibodies were used: KL1, directed to high molecular weight keratins, and KL4, specific for high and medium molecular weight polypeptides. In vivo, KL1 exclusively binds to Hassall's corpuscles of five mammalian species including mouse, rat, guinea-pig, rabbit and pig. Thus KL1 appears as an exclusive marker of Hassall's corpuscles in a large number of mammals. In vitro, thymic epithelial cells gave rise in certain species to Hassall's corpuscles. In contrast to its in vivo reactivity, KL1 never labelled Hassall's corpuscles developed in vitro. These data strongly support the following conclusions: (1) Hassall's corpuscles derive from medullary epithelial cells; (2) they represent advanced stages of thymic epithelial maturation; (3) thymic epithelial cell differentiation is impaired in vitro. Furthermore, this study provides additional evidence that thymic epithelium heterogeneity reflects different stages in epithelial maturation.