Thymic Accessory Cells, Including Dendritic Type Antigen Presenting Cells, within the Mammalian Thymic Microenvironment

Abstract

During mammalian ontogenesis, the thymic “pure” endodermal epithelial anlage develops and differentiates into a complex cellular microenvironment. Beginning the 7–8th week of intrauterine development, thymic epithelial cells chemotactically regulate (induce) numerous waves of migration of stem cells into the thymus, including the CD34⁺, yolk sac-derived, committed hematopoietic stem cells. In vitro experiments have established that CD34⁺ CD38^dim human thymocytes differentiate into T lymphocytes when co-cultured with mouse fetal thymic organs. Hematopoietic stem cells for myeloid and thymic stromal dendritic cells (DCs) are present within the minute population of CD34⁺ progenitors within the mammalian thymus. The common myeloid, DC, natural killer (NK) and T lymphocyte progenitors have been also identified within the CD34⁺ stem cell population in the human thymus. Interactions between the endocrine and immune systems have been reported in various regions of the mammalian body including the anterior pituitary (AP), the skin, and the central (thymus) and peripheral lymphatic system. The network of bone marrow derived DCs is a part of the reticuloendothelial system (RES) and DCs represent the cellular mediators of these regulatory endocrine-immune interactions. Folliculo-stellate cells (FSC) in the AP, Langerhans cells (LCs) in the skin and lymphatic system, “veile” cells, lympho-dendritic and interdigitating cells (IDCs) in a number of tissues comprising the lymphatic system are the cell types of the DC meshwork of “professional” antigen presenting cells (APCs). Most of these cells express the immunocytochemical markers S-100, CD1, CD45, CD54, F418, MHC class I and II antigens, Fc and complement receptors. FSCs are non-hormone-secreting cells which communicate directly with hormone producing cells, a form of neuro-endocrine-immune regulation. As a result, an attenuation of secretory responses follows stimulation of these cells. FSCs are also the cells in the AP producing IL-6, and they have also been identified as the interferon-γ responsive elements. FSCs also express lymphatic DC markers, such as DC specific aminopeptidase, leucyl-β-naphthylaminidase, non-specific esterase, MHC class I and II molecules and various other lymphatic immunological determinants [platelet derived growth factor-α chain (PDGF-α chain), CD13, CD14 and L25 antigen]. There is strong evidence that such DCs in the AP, and similar ones in the developing thymus and peripheral lymphatic tissue are the components of a powerful “professional” antigen presenting DC network. These APCs contain a specialized late endocytic compartment, MIIC (MHC class II-enriched compartment), that harbors newly synthesized MHC class II antigens en route to the cell membrane. The limiting membrane of MIIC can fuse directly with the cell membrane, resulting in release of newly secreted intracellular MHC class II antigen containing vesicles (exosomes). DCs possess the ability to present foreign peptides complexed with the MHC molecules expressed on their surfaces to naive and resting T cells. There are a number of “molecular couples” that influence DC and T lymphocyte interaction during antigen presentation: CD11/CD18 integrins, intercellular adhesion molecules (ICAMs), lymphocyte function associated antigen 3 (LFA-3), CD40, CD80/B7-1, CD86/B7-2, and heat-stable antigen. The “molecular couples” are involved in adhesive or costimulatory regulations, mediating an effective binding of DCs to T lymphocytes and the stimulation of specific intercellular communications. DCs also provide all of the known co-stimulatory signals required for activation of unprimed T lymphocytes. It has been defined that DCs initiate several immune responses, such as the sensitization of MHC-restricted T lymphocytes, resistance to infections and neoplasms, rejection of organ transplants, and the formation of T-dependent antibodies. In addition, DCs and specialized epithelial tissue structures (such as “the nursing” thymic epithelial cells — TNCs) may also be involved in direct, cryptocrine-type cell to cell interactions with the epithelial cells of the thymus. TNCs regulate the development of immature thymocytes into immunocompetent T lymphocytes by emperipolesis, a highly specialized form of cell-cell interaction in which immature thymocytes are engulfed by large thymic RE cells. TNCs in vitro are capable to rescue an early subset of CD4⁺ CD8⁺ thymocytes from apoptosis at 32°C, the temperature at which binding and internalization were identified. This thymocyte subpopulation later matured to a characteristic IP at the double positive stage of T lymphocyte differentiation that is indicative of positive selection