Cellular Interactions in Thymocyte Development

Abstract

Interactions between stromal cells and thymocytes play a crucial role in T cell development. The thymic stroma is complex and consists of epithelial cells derived from the pharyngeal region during development, together with macrophages and dendritic cells of bone marrow origin. In addition, fibroblasts and matrix molecules permeate the whole framework. It is now apparent that these individual stromal components play specialized roles at different stages of T cell differentiation. Thus, at the early CD4-8- stage of development, T cell precursors require fibroblast as well as epithelial cell interactions. Later, at the CD4+8+ stage, as well as providing low avidity TCR/MHC-peptide interactions, thymic epithelial cells have been shown to possess unique properties essential for positive selection. Dendritic cells, on the other hand, are probably efficient mediators of negative selection, but they may not be solely responsible for this activity. Alongside the functional roles of stromal cells, considerable progress is being made in unraveling the nature of the signaling pathways involved in T cell development. Identification of the pre-T cell receptor (pre-TCR) and associated signaling molecules marks an important advance in understanding the mechanisms that control gene rearrangement and allelic exclusion. In addition, a better understanding of the signaling pathways that lead to positive selection on the one hand and negative selection on the other is beginning to emerge. Many issues remain unresolved, and some are discussed in this review. What, for example, is the nature of the chemotactic factor(s) that attract stem cells to the thymus? What is the molecular basis of the essential interactions between early thymocytes and fibroblasts, and early thymocytes and epithelial cells? What is special about cortical epithelial cells in supporting positive selection? These and other issues are ripe for analysis and can now be approached using a combination of modern molecular and cellular techniques.

Preferential Recognition of Self Antigens Despite Normal Thymic Deletion of CD4+CD25+ Regulatory T Cells

“…The majority, if not all, of thymic deletion depends on MHC/peptide complexes expressed by thymic APCs, in particular by dendritic cells (1,37). In bone marrow chimeras expressing MHC/ peptide complexes on radioresistant cells but not on cells of hematopoietic origin, a 2-to 3-fold increased generation of mature thymocytes was observed (2).…”

Impaired migration of NOD mouse thymocytes: a fibronectin receptor‐related defect

“…Since intrathymic T cell development occurs concomitantly to migratory activity [23,24], we and others studied intrathymic interactions involving ECM ligands and receptors [25,26]. The fibronectin receptors very late antigen (VLA)-4 and VLA-5 are relevant in intrathymic T cell development [27][28][29][30], and likely participate in the control of apoptosis [31][32][33].…”

Autonomous and extrinsic regulation of thymopoiesis inhuman immune system (HIS) mice

“…On the other hand, interaction of haematopoietic precursors with murine thymic epithelial cell (TEC) ligands or soluble factors during thymopoiesis and subsequent selection of T cells on murine major histocompatibility complexes (MHC) may generate suboptimal signals for T-cell maintenance. T-cell development depends on instructive temporal-spatial signals provided by a resident cellular network known as thymic stroma [6,7]. TECs represent the main thymic stromal compartment in the pre-involution thymus and constitute a multifunctional platform that supports thymocyte commitment, survival, division, migration and selection.…”

“…TECs are classically divided into two specialized functional subsets, cortical (cTECs) and medullary (mTECs). While cTECs are important at early stages of T-cell development and mediate positive selection, mTECs are critical at later stages governing negative selection and providing survival signals to mature single-positive (SP) thymocytes [6,8,9]. The generation of these two functionally competent TEC compartments is a prerequisite for normal thymopoiesis.…”

“…The recent advances in the development of HIS mice provide a new model to experimentally dissect human lymphocyte biology that may eventually allow us to bridge the knowledge gap between murine and human in vivo studies of immune responses. T-cell development depends on instructive temporal-spatial signals provided by a resident cellular network known as thymic stroma [6,7]. TECs represent the main thymic stromal compartment in the pre-involution thymus and constitute a multifunctional platform that supports thymocyte commitment, survival, division, migration and selection.…”