Interferons Mediate Terminal Differentiation of Human Cortical Thymic Epithelial Cells

Abstract

In the thymus, epithelial cells comprise a heterogeneous population required for the generation of functional T lymphocytes, suggesting that thymic epithelium disruption by viruses may compromise T-cell lymphopoiesis in this organ. In a previous report, we demonstrated that in vitro, measles virus induced differentiation of cortical thymic epithelial cells as characterized by (i) cell growth arrest, (ii) morphological and phenotypic changes, and (iii) apoptotis as a final step of this process. In the present report, we have analyzed the mechanisms involved. First, measles virus-induced differentiation of thymic epithelial cells is shown to be strictly dependent on beta interferon (IFN-␤) secretion. In addition, transfection with double-stranded RNA, a common intermediate of replication for a broad spectrum of viruses, is reported to similarly mediate thymic epithelial cell differentiation through IFN-␤ induction. Finally, we demonstrated that recombinant IFN-␣, IFN-␤, or IFN-␥ was sufficient to induce differentiation and apoptosis of uninfected thymic epithelial cells. These observations suggested that interferon secretion by either infected cells or activated leukocytes, such as plasmacytoid dendritic cells or lymphocytes, may induce thymic epithelium disruption in a pathological context. Thus, we have identified a new mechanism that may contribute to thymic atrophy and altered T-cell lymphopoiesis associated with many infections.The thymus is a primary lymphoid organ that ensures Tlymphocyte differentiation from bone marrow-derived progenitors (for reviews, see references 3 and 21). Thymic microenvironments are composed of a network of thymic epithelial cells (TEC), present in both the cortex and the medulla, and hematopoietic cells such as macrophages and dendritic cells. Thymocytes migrate, while differentiating, through distinct microenvironments in the subcapsular cortex, the deep cortex, the cortico-medullary junction, and the medulla, where they are finally released, as mature T cells, into the bloodstream. Thymic microenvironments sustain thymocyte development, providing survival, proliferation, and differentiation signals that allow T-cell receptor gene rearrangements. Moreover, interaction of immature T cells with thymic microenvironments ensures the production of major histocompatibility complex-restricted, self-tolerant T cells. Within the cortex, positive selection of immature T cells expressing functional T-cell receptor is mediated mainly by cortical TEC, whereas in the medulla, negative selection of developing autoreactive T cells is ensured by antigen-presenting cells of hematopoietic origin and, to a lesser extent, the TEC subset. Thus, thymic microenvironments support thymocyte survival and differentiation into mature T cells.Among the factors that profoundly affect T-cell lymphopoiesis is infection by measles virus (MV), a single-stranded RNA (ssRNA) virus from the Paramyxoviridae family that induces a severe lymphopenia and immunosuppression in humans (16). MV initially replicates in the re...

Measles Virus (MV) Nucleoprotein Binds to a Novel Cell Surface Receptor Distinct from FcγRII via Its C-Terminal Domain: Role in MV-Induced Immunosuppression

“…At different times postinfection, cell-free supernatants were collected for enzyme-linked immunosorbent assays (ELISAs) and for infectious MV particle production. The median 50% tissue culture infective dose (TCID 50 ) was calculated as previously described (61). For ELISA assays, cell-free supernatants were UV inactivated (30 min at 254 nm) and twofold serially diluted.…”

Reversible Blockade of Thymic Output: An Inherent Part of TLR Ligand-Mediated Immune Response

“…2). The decrease in DN proliferation could result from the killing of thymic epithelial cells (TECs) by type I IFNs (52). TECs play an important role on early stages of thymic development as they have been shown to play a critical role in regulating the proliferation and survival of the most immature thymocytes through the release of different mediators including, IL-7 and keratinocyte growth factor (53)(54)(55).…”

Stimulated plasmacytoid dendritic cells impair human T-cell development

“…30 In addition, it was shown that IFN-␣ mediates terminal differentiation and subsequent apoptosis of human thymic epithelial cells, which may contribute to thymic atrophy. 31 Because activated pDCs are known to produce high amounts of IFN-␣, the activation of thymic pDCs could potentially adversely affect T-cell development. Here we examined whether pDCs have an impact on early IL-7-induced human T-cell development.…”