Thymocyte migration: an affair of multiple cellular interactions?

Cell migration is a crucial event in the general process of thymocyte differentiation. The cellular interactions involved in the control of this migration are beginning to be defined. At least chemokines and extracellular matrix proteins appear to be part of the game. Cells of the thymic microenvironment produce these two groups of molecules, whereas developing thymocytes express the corresponding receptors. Moreover, although chemokines and extracellular matrix can drive thymocyte migration per se, a combined role for these molecules appears to contribute to the resulting migration patterns of thymocytes in their various stages of differentiation. The dynamics of chemokine and extracellular matrix production and degradation is not yet well understood. However, matrix metalloproteinases are likely to play a role in the breakdown of intrathymic extracellular matrix contents. Thus, the physiological migration of thymocytes should be envisioned as a resulting vector of multiple, simultaneous and/or sequential stimuli involving chemokines, adhesive and de-adhesive extracellular matrix proteins, as well as matrix metalloproteinases. Accordingly, it is conceivable that any pathological change in any of these loops may result in the alteration of normal thymocyte migration. This seems to be the case in murine infection by the protozoan parasite Trypanosoma cruzi, the causative agent of Chagas' disease. A better knowledge of the physiological mechanisms governing thymocyte migration will provide new clues for designing therapeutic strategies targeting developing T cells

The conveyor belt hypothesis for thymocyte migration: participation of adhesion and de-adhesion molecules

Thymocyte differentiation is the process by which bone marrow-derived precursors enter the thymus, proliferate, rearrange the genes and express the corresponding T cell receptors, and undergo positive and/or negative selection, ultimately yielding mature T cells that will represent the so-called T cell repertoire. This process occurs in the context of cell migration, whose cellular and molecular basis is still poorly understood. Kinetic studies favor the idea that these cells leave the organ in an ordered pattern, as if they were moving on a conveyor belt. We have recently proposed that extracellular matrix glycoproteins, such as fibronectin, laminin and type IV collagen, among others, produced by non-lymphoid cells both in the cortex and in the medulla, would constitute a macromolecular arrangement allowing differentiating thymocytes to migrate. Here we discuss the participation of both molecules with adhesive and de-adhesive properties in the intrathymic T cell migration. Functional experiments demonstrated that galectin-3, a soluble ß-galactoside-binding lectin secreted by thymic microenvironmental cells, is a likely candidate for de-adhesion proteins by decreasing thymocyte interaction with the thymic microenvironment

The thymic nurse cell complex: an in vitro model for extracellular matrix-mediated intrathymic T cell migration

The thymus is a primary lymphoid organ in wich bone narrow-derived T cell precursors undergo a complex maturation process in the context of the thymic microenvironment, represented by non-lymphoid cells and extracellular matrix (ECM) components. The thymic epithelial cells are the major cellular component of the thymic microenvironment, and influence different aspects of thymocyte differentiation, via cell-cell interactions and secretion of soluble factors, such as thymic hormones. The thymic nurse cell (TNC) complexes are multicellular lymphoepithelial structures formed by one thymic epithelial cell harboring 2-200 thymocytes, primary bearing the CD4/CD8 double-positive phenotype. TNCs probably create a special microenvironment for thymocyte differentiation and/or proliferation, with thymocytes being exposed to major histocompatibility complex (MHC) antigens and thymic hormones. Such differentiation parallels cell migration into and out of the complex. We showed the expression of ECM components and respective receptors by TNCs, and that interactions between the epithelial component of TNC and TNC-lymphocytes can be modulated by ECM components and respective receptors. Moreover, we demonstrated that intrinsic as well as extrinsic biological circuits can be involved in the control of such ECM-mediated thymic epithelial cell (TEC)/thymocyte interactions. For example, interferon-gamma can biphasically modulate the expression of ECM ligands and receptors by TEC, with results in corresponding modulation of their ability to interact with TNC-thymocytes. Additionally, hormones such as triiodothyronine, prolactin and growth hormone can influence the degree of these lymphocyte/epithelial cell adhesive interactions. Lastly, we recently furnished evidence for a de-adhesive mechanism within TNC aparently mediated by galectin 3 (an endogenous soluble beta-galactoside-binding lectin). Taken together, our data strongly indicate that thymic nurse cells can be regarded as an in vitro model for intrathymic T cell migration, particularly with respect to those events mediated by the extracellular matrix.

Carbohydrate-binding proteins in cell-matrix interactions

1. Carbohydrate-dependent interactions have been more extensively studied during the last decade. Althought the roles of carbohydrates in cellular functions are still poorly understood, the finding of carbohydrate-binding proteins in animal cells opened a great number of perspectives. 2. Animal lectins are associated with tumor progression, playing a key role in neoplastic cell interactions with endothelial cells and extracellular matrix glycoproteins such as laminin. 3. Here, we review the role of animal lectins in the migrating phenotype of neoplastic cells and normal cells such as T-lymphocytes