Intrinsic and extrinsic circuits controling the thymic microenvironment

RESUMO

The thymic microenvironment plays a key role in the general process of intrathymic T cell differentiation, that ultimately yields the vast majority of the T cell repertoire. This nonlymphoid compartment is mostly composed of thymic epithelial cells (TEC), that together with dendritic cells, macrophages and elements of the extracellular matrix form a tridimensional network in which context thymocyte differentiation occurs. Microenvironmental cells modulate intrathymic T cell diferentiation by means of a variety of secretory products, comprising several cytokines and thymic hormones, as well as cell-cell interactions, including those mediated by MHC products, adhesion molecules and extracellular matrix ligands and receptors. When studying the physiology of the thymic microenvironment one should take into account the existence of intrinsic and extrinsic circuits controlling it. For example, we showed that interferon-gamma (IFN-gamma), a thymocyte-derived cytokine, is able to pleiotropically modulate both epithelial and dendritic cells of the thymus. Besides enhancing the expression of MHC class two molecules on these cell types, IFN-gamma regulates, in a dose-dependent biphasic manner, the expression of extracellular matrix ligands and receptors that implies a corresponding modulation on the ability of thymocytes to adhere onto IFN-gamma-treated TEC cultures. In addition, extrinsic endogenous circuits appear to continuously influence the thymic microenvironment. We evidenced that steroid, thyroid and pituitary hormones can modulate several aspects of TEC physiology including thymic hormone secretion, cytokeratin expression, cell growth as well as expression of extracellular matrix ligands and receptors. Latter effects directly intervene, at least as assessed by in vitro models, in TEC/thymocyte interactions. Other endogenous situations such as aging and autoimmunity also influence the thymic microenvironment. For example, in both conditions we showed a decay in thymic hormone secretion, changes in the expression of cortical and medullary cytokeratins, and an increase in extracellular matrix. Furthermore, the thymic microenvironment is modulated by stimuli from the environmental world such as infectious agents. In the Trypanosoma cruzi model, we noticed that both TEC and thymic macrophages are infected in vivo and in vitro...