The conveyor belt hypothesis for thymocyte migration: participation of adhesion and de-adhesion molecules (original) (raw)
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Journal of leukocyte biology, 2004
Cell migration is crucial for thymocyte differentiation, and the cellular interactions involved now begin to be unraveled, with chemokines, extracellular matrix (ECM) proteins, and their corresponding receptors being relevant in such oriented movement of thymocytes. This notion derives from in vitro, ex vivo, and in vivo experimental data, including those obtained in genetically engineered and spontaneous mutant mice. Thymic microenvironmental cells produce both groups of molecules, whereas developing thymocytes express chemokine and ECM receptors. It is important that although chemokines and ECM proteins can drive thymocyte migration per se, a combined role of these molecules likely concurs for the resulting migration patterns of thymocytes in their various differentiation stages. In this respect, among ECM moieties, there are proteins with opposing functions, such as laminin or fibronectin versus galectin-3, which promote, respectively, adhesion and de-adhesion of thymocytes to the thymic microenvironment. How chemokines and ECM are produced and degraded remains to be more clearly defined. Nevertheless, matrix metalloproteinases (MMPs) likely play a role in the intrathymic ECM breakdown. It is interesting that these molecules also degrade chemokines. Thus, the physiological migration of thymocytes should be conceived as a resulting vector of multiple, simultaneous, or sequential stimuli, involving chemokines, adhesive, and de-adhesive ECM proteins. Moreover, these interactions may be physiologically regulated in situ by matrix MMPs and are influenced by hormones. Accordingly, one can predict that pathological changes in any of these loops may result in abnormal thymocyte migration. This actually occurs in the murine infection by the protozoan Trypanosoma cruzi, the causative agent of Chagas disease. In this model, the abnormal release of immature thymocytes to peripheral lymphoid organs is correlated with the higher migratory response to ECM and chemokines. Lastly, the fine dissection of the mechanisms governing thymocyte migration will provide new clues for designing therapeutic strategies targeting developing T cells. The most important function of the thymus is to generate T lymphocytes, which once leaving the organ, are able to colonize specific regions of peripheral lymphoid organs, the T cell zones, where they can mount and regulate cell-mediated, immune responses. This intrathymic T cell differentiation is a complex sequence of biological events, comprising cell proliferation, differential membrane protein expression, gene rearrangements, massive programmed cell death, and cell migration. In this review, we will focus on the mechanisms involved in controlling the migration of thymocytes, from the entrance of cell precursors into the organ to the exit of mature T cells toward peripheral lymphoid organs. Nevertheless, to better comprehend this issue, it appeared worthwhile to briefly comment on some key aspects of thymocyte differentiation and the tissue context in which it takes place, the thymic microenvironment. J. Leukoc. Biol. 75: 951-961; 2004.
Extracellular matrix proteins in intrathymic T-cell migration and differentiation?
Immunology Today, 1993
T-cell differentiation is the process by which bone marrow-derived precursors enter the thymus and develop into T cells. They expand, rearrange and express the Tcell receptor (TCR) genes and a number of other surface molecules, and if they survive positive and negative selection, are released into the peripheryL As they differentiate, th]}anocytes migrate within the thymic lobules, from the cortex to the medulla. The molecular basis for such migration process probably involves sequential interactions mediated by membrane receptors and co-receptors expressed by thymocytes and microenvironmental cells. There are two, nonexclusive, models for this process (Fig. 1): either direct cell-cell contact, allowing thymocytes to move onto the cytoplasmic processes of microenvironmental cells, or bridging by ext~acellular matrix (ECM) elements, establishing transient links between thymocyte and m~cr~nvh-onmental--"---~ t:en memorane receptors. Q Fig. 1. Representation of two distinct cell-cell interactions involving differentiating tlrymocytes and tbymic microenvironmental cells. (a) Shows tbymo-~. es establishing interaaions via receptors that directly bind counter-receptors in the microenvirGnmental cell. Alternatively (b) shows the interactions mediated by an ECM molecule.
1996
T cell development in the thymus requires the establishment of stable interactions with cellselecting elements such as the cortical epithehum followed by a regulated movement of selected progenitors to the medulla. Cell adhesion and migration are mediated by integrins in a number of biological systems though little is known regarding their function in the thymus. We demonstrated previously that immature CD31~ l~ double positive human thymocytes adhere avidly to FN via the integrin, VLA4. We now demonstrate that the interaction of mature CD3hiCD69 hi thymic subsets with FN triggers migration rather than firm adhesion. Migration requires the engagement of VLA4 in cooperation with VLA5 and both receptors regulate the persistence and directionality of movement. While migration capability is linked to maturation state, ligand concentration determines the efficiency of migration. In fact, FN and the alternatively sphced CS1 site are predominant in the thymic medulla, suggesting an instructive role of this ECM protein in vivo. Our studies identify a novel VLA4 and VLA5/FNmediated pathway likely to be involved in regulating cell traffic between the cortex and medulla of the thymus. Moreover, the data provides evidence that VLA4 exists in at least two functional states at distinct stages ofT cell development. While different states of VLA4 activation have been described on cell lines, this represents the first evidence supporting a biological significance for this integrin property. p ositioning of developing thymocytes within the thymic cortex and medulla as well as the regulation of their ability to move from one region to another are crucial to T cell differentiation. Thus a stable interaction with cortical epithelial cells facihtating the recognition of MHC/peptide complexes is a prerequisite for the positive selection of immature double positive T cells (1). In fact, there is evidence that positive selection within the cortex is limited by contact with these selecting elements (2, 3) underscoring the importance of migratory events leading T cell progenitors to the epithehum. Subsequent events of maturation, including negative selection, appear to occur in the medulla involving bone marrow-derived antigen-presenting cells as well as a phenotypically distinct medullary epithelium (4). Implicit in these compartment-specific events is the programmed detachment of developing thymocytes from the cortical epithelium and the regulated movement of those committed to the mature single positive phenotype to the medulla. While much has been learned about the function of the T cell receptor (TCPQ and the costimulatory mole-cules, CD4 and CD8, these molecules cannot directly mediate stable cell-cell adhesion or migration. In contrast, the role of interactions mediated by integrin adhesion molecules expressed by thymocytes with extracellular matrix (ECM) 1 proteins such as fibronectin (FN) in thymocyte motihty, has not been elucidated.
Impaired migration of NOD mouse thymocytes: a fibronectin receptor-related defect
European Journal of Immunology, 2004
We previously showed intrathymic alterations in non-obese diabetic (NOD) mice, including the appearance of giant perivascular spaces, filled with mature thymocytes, intermingled with an extracellular matrix network. This raised the hypothesis of a defect in thymocyte migration with partial arrest of exiting thymocytes in the perivascular spaces. Herein, we investigated the expression of receptors for fibronectin [very late antigen (VLA)-4 and VLA-5] and laminin (VLA-6), known to play a role in thymocyte migration. When compared with two normal and one other autoimmune mouse strains, a decrease of VLA-5 expression in NOD thymocytes was noticed, being firstly observed in late CD4/CD8 double-negative cells, and more pronounced in mature CD4 + and CD8 + thymocytes. Functionally, thymocyte exit from the lymphoepithelial complexes, the thymic nurse cells, was reduced. Moreover, NOD thymocyte adhesion to thymic epithelial cells as well as to fibronectin was diminished, and so was the migration of NOD thymocytes through fibronectin-containing transwell chambers. In situ, intra-perivascular space thymocytes were VLA-5-negative, suggesting a correlation between the thymocyte arrest within these structures and loss of VLA-5 expression. Overall, our data reveal impairment in NOD thymocyte migration, and correspond to the first demonstration of a functional fibronectin receptor defect in the immune system. Abbreviations: DN: Double-negative DP: Doublepositive ECM: Extracellular matrix PVS: Perivascular space RT: Reverse transcription RTE: Recent thymic emigrants SP: Single-positive TEC: Thymic epithelial cells TNC: Thymic nurse cells VLA: Very late antigen 1578
Intrathymic T-cell migration: a combinatorial interplay of extracellular matrix and chemokines?
Trends in Immunology, 2002
From the entrance of T-cell precursors into the thymus to the exit of mature cells from the organ, a vast body of interactions promotes the complex process of T-cell differentiation, which is already described in textbooks [1], and is not within the scope of this review. What is relevant herein is the fact that thymocyte differentiation occurs as cells migrate within the thymic lobules. As illustrated in , most of the immature thymocytes, including those bearing the phenotypes T-cell receptor (TCR) − CD3 − CD4 − CD8 − and TCR low CD3 low CD4 + CD8 + are located cortically, whereas mature TCR high CD3 high CD4 + CD8 − and TCR high CD3 high CD4 − CD8 + cells (that will normally leave the thymus and traffic to peripheral lymphoid organs) are found in the medulla. also shows that during the course of their journey within the thymus, developing thymocytes encounter cortical and medullary microenvironments, through distinct cell-cell and cell-matrix interactions . Cell migration is thus a crucial event for intrathymic T-cell differentiation. A series of recent data led us to revisit this field and propose that chemokines might act in concert with extracellular matrix (ECM), resulting in the migration of a given cell subset, either within the thymus or at the entrance into and/or exit from the organ. Moreover, as seen in some of the examples discussed here, modulation of cell migration-related molecules might result in changes in thymocyte differentiation.
Galectin-3 modulates carbohydrate-dependent thymocyte interactions with the thymic microenvironment
European journal of immunology, 2002
The process of thymocyte differentiation occurs within the context of the thymic microenvironment, in which T cell precursors interact with thymic microenvironmental cells and extracellular matrix. Here we studied the expression of galectin-3, a g -galactoside binding lectin, in the thymus of young adult mice. Galectin-3 was found mainly in the medulla and to a lesser extent in the cortex. We further showed that distinct microenvironmental elements, such as thymic epithelial cells, the epithelial component of thymic nurse complexes and phagocytic cells of the thymic reticulum produce, secrete and accumulate galectin-3 on the cell surface. Functionally, galectin-3-enriched medium inhibited in vitro thymocyte interactions with thymic microenvironmental cells, accelerated the release of thymocytes from thymic nurse cells and inhibited the reconstitution of these lymphoepithelial complexes. These effects were blocked by exogenous lactose ), but not melibiose (Gal § 1-6Glc), and by a monospecific anti-galectin-3 antibody. Recombinant galectin-3 also inhibited thymocyte/thymic epithelial cell interactions. Our data indicate that intrathymically produced galectin-3 disrupts thymocyte/microenvironmental cell interactions, thus acting as a deadhesion molecule.
Multivectorial Abnormal Cell Migration in the NOD Mouse Thymus
The Journal of Immunology, 2008
We previously described a fibronectin/VLA-5-dependent impairment of NOD thymocyte migration, correlated with partial thymocyte arrest within thymic perivascular spaces. Yet, NOD thymocytes still emigrate, suggesting the involvement of other cell migration-related alterations. In this context, the aim of this work was to study the role of extracellular matrix ligands, alone or in combination with the chemokine CXCL12, in NOD thymocyte migration. Intrathymic contents of CXCL12, fibronectin, and laminin were evaluated by immunohistochemistry while the expression of corresponding receptors was ascertained by flow cytometry. Thymocyte migration was measured using Transwell chambers and transendothelial migration was evaluated in the same system, but using an endothelial cell monolayer within the chambers. NOD thymocytes express much lower VLA-5 than C57BL/6 thymocytes. This defect was particularly severe in CD4 ؉ thymocytes expressing Foxp3, thus in keeping with the arrest of Foxp3 ؉ cells within the NOD giant perivascular spaces. We observed an enhancement in CXCL12, laminin, and fibronectin deposition and colocalization in the NOD thymus. Furthermore, we detected altered expression of the CXCL12 receptor CXCR4 and the laminin receptor VLA-6, as well as enhanced migratory capacity of NOD thymocytes toward these molecules, combined or alone. Moreover, transendothelial migration of NOD thymocytes was diminished in the presence of exogenous fibronectin. Our data unravel the existence of multiple cell migration-related abnormalities in NOD thymocytes, comprising both down-and up-regulation of specific responses. Although remaining to be experimentally demonstrated, these events may have consequences on the appearance of autoimmunity in NOD mice.
International journal of clinical and experimental pathology, 2010
The effect of exogenous Gal-1 on cellular response and adhesion molecule expression was investigated in a classical model of acute inflammation induced by zymosan. C57BL6 mice, treated or not with human recombinant (hr) Gal-1, received i.p. injection of zymosan and peritoneal exudate, blood and mesentery were processed for cellular, biochemical, light and electron microscopic analysis after 4 and 24 h. Zymosan peritonitis provoked the expected signs of inflammation at 4 h, including a significant increase in extravasated PMNs in the mesentery and peritoneal exudate, mirrored by blood neutrophilia. These changes subsided after 24 h. Ultrastructural immunocytochemical analysis of PMNs showed significant Gal-1 expression and co-localization with L-selectin and β2-integrin in the plasma membrane and cytoplasm. Pharmacological treatment with hrGal-1 at 4 h produced an inhibition of PMN migration, associated with diminished expression of adhesion molecules, particularly β2-integrin, and T...
A Novel Adhesion Molecule in the Murine Thymic Microenvironment: Functional and Biochemical Analysis
Developmental Immunology, 1992
The rat monoclonal antibody (mAb) 4F1, raised against mouse thymic stromal cells, recognizes cortical epithelium in tissue sections of mouse thymus; however, in flow cytometry, activated leucocytes (T cells, B cells, and macrophages) and transformed thymocytes are also positive for the 4Fl-antigen (4F1-Ag). Western blotting, under both reducing and nonreducing conditions, demonstrates that the molecule to which 4F1 binds is expressed in four forms, 29, 32, 40, and 43 kD, all of which carry N-linked carbohydrate; and that the structure is identical on epithelium and lymphocytes. The 4F1-Ag on cortical epithelium is partially sensitive to PI-PLC treatment, whereas on transformed epithelial and lymphoid cell lines, it was resistant to this enzyme. The molecule, therefore, may exist in both transmembrane and phosphoinositol-linked forms. In functional blocking experiments, mAb 4F1 gave inhibition of both T-cell proliferation in MLR and of cytotoxic T-cell killing of alloantigenic targets; it also blocked adhesion of transformed thymocytes to thymic epithelial cells in vitro. These molecular and functional characteristics suggest that the 4F1-Ag is a novel adhesion molecule that may be involved both in intrathymic T lymphocyte differentiation and in peripheral T-cell function. Thymus, thymocytes, lymphocyte activation, PI linkage. 'Thymoma lymphoid cells and normal BALB/c thymocytes (10") stained in suspension using the immunofluorescence technique and analyzed by flow cytofluorimetry. The percentage of cells stained by other mAbs such anti-IA, anti-CD4, anti-CD8, and anti-Thyl.2 shown in comparison. Data from three independent experiments (mean %+standard deviation). bTypical of the 2/14 mice.
ISRN Inflammation, 2013
Monocyte migration into tissues, an important event in inflammation, requires an intricate interplay between determinants on cell surfaces and extracellular matrix (ECM). Galectin-3 is able to modulate cell-ECM interactions and is an important mediator of inflammation. In this study, we sought to investigate whether interactions established between galectin-3 and ECM glycoproteins are involved in monocyte migration, given that the mechanisms by which monocytes move across the endothelium and through the extravascular tissue are poorly understood. Using the in vitro transwell system, we demonstrated that monocyte migration was potentiated in the presence of galectin-3 plus laminin or fibronectin, but not vitronectin, and was dependent on the carbohydrate recognition domain of the lectin. Only galectin-3-fibronectin combinations potentiated the migration of monocytederived macrophages. In binding assays, galectin-3 did not bind to fibronectin, whereas both the full-length and the truncated forms of the lectin, which retains carbohydrate binding ability, were able to bind to laminin. Our results show that monocytes migrate through distinct mechanisms and selective interactions with the extracellular matrix driven by galectin-3. We suggest that the lectin may bridge monocytes to laminin and may also activate these cells, resulting in the positive regulation of other adhesion molecules and cell adhesion to fibronectin.