Enhancement of stromal cell-derived factor-1alpha-induced chemotaxis for CD4/8 double-positive thymocytes by fibronectin and laminin in mice (original) (raw)
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Differential Chemotactic Behavior of Developing T Cells in Response to Thymic Chemokines
Blood
Differentiation-dependent thymocyte migration in the thymus may be important for T lymphopoiesis and might be regulated by thymic chemoattractants. We examined modulation of chemotactic responsiveness of thymocyte subsets during their early to late stages of development in response to 2 thymus-expressed chemokines, SDF-1 and CKβ-11/MIP-3β/ELC. SDF-1 shows chemotactic preference for immature thymocytes (subsets of triple negative thymocytes and double positive [DP] subset) over mature single positive (SP) thymocytes. CKβ-11/MIP-3β/ELC shows low chemotactic activity on the immature thymocytes, but it strongly attracts mature SP thymocytes, effects opposite to that of SDF-1. SDF-1–dependent chemoattraction of immature thymocytes is not significantly desensitized by a negative concentration gradient of CKβ-11/MIP-3β/ELC, and chemoattraction of mature SP thymocytes to CKβ-11/MIP-3β/ELC is not antagonized by SDF-1, demonstrating that these two chemokines have different chemoattractant pre...
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.
The Journal of Immunology, 2000
The chemoattractant activity of macrophage-derived chemokine (MDC), EBI1-ligand chemokine (ELC), and secondary lymphoid tissue chemokine (SLC) on human thymocytes was analyzed. Both ELC and SLC caused the accumulation of CD4 ؉ CD8 ؊ or CD4 ؊ CD8 ؉ CD45RA ؉ thymocytes showing high CD3 expression. By contrast, a remarkable proportion of MDC-responsive thymocytes were CD4 ؉ CD8 ؉ cells exhibiting reduced levels of CD8 or CD4 ؉ CD8 ؊ cells showing CD3 and CD45R0, but not CD45RA. MDC-responsive thymocyte suspensions were enriched in cells expressing the MDC receptor, CCR4, selectively localized to the medulla, and in CD30 ؉ cells, whereas ELC-responsive thymocytes never expressed CD30. Reactivity to both MDC and ELC was localized to cells of the medullary areas, but never in the cortex. Double immunostaining showed no reactivity for either MDC or ELC by T cells, macrophages, or mature dendritic cells, whereas many medullary epithelial cells were reactive to MDC or ELC. However, MDC reactivity was consistently localized to the outer wall of Hassal's corpuscles, whereas ELC reactivity was often found in cells surrounding medullary vessels, but not in Hassal's corpuscles. Moreover, while most MDC-producing cells also stained positive for CD30L, this molecule was never found on ELC-producing cells. We suggest therefore that CD30L-expressing MDC-producing medullary epithelial cells attract CCR4-expressing thymocytes, thus favoring the CD30/CD30L interaction, and therefore the apoptosis, of cells that are induced to express CD30 by autoantigen activation. By contrast, ELC production by CD30L-lacking medullary epithelial cells may induce the migration into periphery of mature thymocytes that have survived the process of negative selection.
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.
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
Thymotaxin: a thymic epithelial peptide chemotactic for T-cell precursors
Proceedings of the National Academy of Sciences, 1988
The embryonic thymus is seeded by invading hemopoietic precursor cells that differentiate intrathymically into T lymphocytes. We have recently reported that avian thymic epithelial cells secrete chemotactic peptides, which provoke oriented migration of hemopoietic precursor cells in vitro. The established rat thymic epithelial cell line IT-45 R1 produced a polypeptide that resolves as a single band in the region of 11 kDa on NaDodSO4/polyacrylamide gels. This molecule, which we have named thymotaxin, induced a chemotactic response in a subpopulation of hemopoietic cells from juvenile rat bone marrow. Responding cells were generated by short-term coculture ofrat bone marrow hemopoietic cells with mouse bone marrow stroma in a steroid-free medium. Cells selected in a chemotactic chamber have a lymphoid or blast cell morphology. The phenotype of the responding cells is Thy-i +, CD4+ and CD8-. In contrast, CD8 T-lymphocyte differentiation antigen was expressed after coculture with embryonic thymic monolayers, suggesting that the responding cells correspond to the precursors colonizing the thymus.
Critical involvement of Tcf-1 in expansion of thymocytes
Journal of immunology (Baltimore, Md. : 1950), 1998
T cell maturation in Tcf-1(-/-) mice deteriorates progressively and halts completely around 6 mo of age. During fetal development thymocyte subpopulations seem normal, although total cell numbers are lower. By 4 to 6 wk of age, obvious blockades in the differentiation of CD4- 8- thymocytes are observed at two distinct stages (CD44+ 25+ and CD44- 25-), both of which are normally characterized by extensive proliferation. This lack of thymocyte expansion and/or differentiation was also observed when Tcf-1(-/-) progenitor cells from the aorta-gonad-mesonephros region (embryonic day 11.5), fetal liver (embryonic day 12.5/14.5), and fetal bone marrow (embryonic day 18.5) were allowed to differentiate in normal thymic lobes (fetal thymic organ cultures) or were injected intrathymically into normal recipients. Despite these apparent defects in thymocyte differentiation and expansion, adult Tcf-1(-/-) mice are immunocompetent, as they generate virus neutralizing Abs at normal titers. Further...
The Journal of Immunology, 2004
We have previously shown that laminin-5 is expressed in the human thymic medulla, in which mature thymocytes are located. We now report that laminin-5 promotes migration of mature medullary thymocytes, whereas it has no effect on cortical immature thymocytes. Migration was inhibited by blocking mAbs directed against laminin-5 integrin receptors and by inhibitors of metalloproteinases. Interactions of thymocytes with laminin-5 induced a strong up-regulation of active metalloproteinase-14. However, we found that thymocytes did not cleave the laminin-5 ␥ 2 chain, suggesting that they do not use the same pathway as epithelial cells to migrate on laminin-5. Interactions of thymocytes with laminin-5 also induced the release of a soluble fragment of CD44 cell surface molecule. Moreover, CD44-rich supernatants induced thymocyte migration in contrast with supernatants depleted in CD44 by immunoadsorption. CD44 cleavage was recently reported to be due to metalloproteinase-14 activation and led to increased migration in cancer cells. Thus, in this study, we show that laminin-5 promotes human mature thymocyte migration in vitro via a multimolecular mechanism involving laminin-5 integrin receptors, metalloproteinase-14 and CD44. These data suggest that, in vivo, laminin-5 may function in the migration of mature thymocytes within the medulla and be part of the thymic emigration process.