The role of the reticulo-epithelial (RE) cell network in the immuno-neuroendocrine regulation of intrathymic lymphopoiesis

The thymus provides an optimal cellular and humoral microenvironment for th e development of immunocompetent T lymphocytes. Although yolk sac derived p re-T, committed hematopoietic stem cells enter the thymus using a homing re ceptor; the immigration process also requires secretion of a peptide, calle d thymotaxin by the cells of the reticulo-epithelial (RE) network of the th ymic cellular microenvironment. The thymic RE cells are functionally specia lized based on their location within the thymic microenvironment. Thus, alt hough subcapsular; cortical, and medullary RE cells are derived from a comm on, endodermal in origin epithelial precursor cell, their unique location w ithin the gland causes their specialization in terms of their immunophenoty pical and in situ physiological proper ties. The subcapsular, endocrine, RE cell layer (giant or nurse cells) is comprised of cells filled with PAS po sitive granules which also express A(2)B(5)/TE4 cell surface antigens and M HC Class I (HLA A,B,C) molecules. In contrast to the medullary RE cells, th ese subcapsular nurse cells also produce thymosins beta 3 and beta 4. The t hymic nurse cells (TNCs) display a neuroendocrine cell specific immunopheno type (IP): Thy-1(+) A(2)B(5)(+) TT+, TE4(+), UJ13/A(+), UJ127.11(+), UJ167. 11(+) UJ181.4(+), and presence of common leukocyte antigen (CLA(+)). Medull ar RE cells display MHC Class II (HLA-DP, HLA-De, HLA- DR) molecule restric tion. These cells also contain transforming growth factor (TGF)-beta type I I receptors and are involved in the positive selection of T cells. Transmis sion electronmicroscopic (TEM) observations have defined four, functional s ubtypes of medullary RE cells: undifferentiated, squamous, villous and cyst ic. All subtypes were connected with desmosomes. The secreted thy nic hormo nes, thymulin, thymosin -alpha 1 and thymopoietin (its short form, thymopen tin or TP5) were detected immunocytochemically to be produced by RE cells. Thymic RE cells also produce numerous cytokines including IL-1, IL-6,. G-CS F, M-CSF, and GM-CSF molecules that likely are important in various stages of thymocyte activation and differentiation. The co-existence of pituitary hormone and neuropeptide secretion [growth hormone (GH) prolactin (PRL) adr enocorticotropic hormone (ACTH), thyroid stimulating hormone (TSH), triiodo thyronine (T-3) somatostatin, oxytocin (OT), follicle stimulating hormone ( FSH), luteinizing hormone (LH), arginine vasopressin (AVP), growth hormone releasing hormone (GHRH), corticotropin releasing hormone (CRH), nerve grow th factor (NGF), vasoactive intestinal peptide (VIP), pro-enkephalin (pro-e nk), and beta-endorphin (beta-end)], as well as production of a number of i nterleukins and growth factors and expression of receptors for all, by RE c ells is an unique molecular biological phenomenon. The thymic RE cell netwo rk is most probably comprised of cells organized into sub-networks - functi onal units composed of RE cells with differing hormone production/hormone r eceptor expression profiles, involved in the various stages of T lymphocyte maturation. Furthermore, it is quite possible that even on the level of in dividual RE cells, the numerous projections associated with a single cell, which engulf developing lymphocytes, ma turing and guiding them in their ma turation, may differ in their hormone production and/or hormone receptor ex pression profile, thus allowing a single cell to be involved in distinct, s eparate steps of the T cell maturation process. Based on our systematic observations of the thymus in humans and other mamm alian species, we suggest that the thymic RE cells represent an extremely i mportant cellular and humoral network within the thymic microenvironment an d are involved in the homeopathic regulation mechanisms of the multicellula r organism, in addition to the presentation of various antigens to developi ng lymphocytes, and providing growth regulatory signals which may range fro m stimulatory to apoptotic signaling within the thymus. Intrathymic T lymph ocyte selection is a complex, multistep process, influenced by sever al fun ctionally specialized RE cells and under immuno-neuroendocrine regulation r eflecting the dynamic changes of the organism.