Molecular mechanisms governing thymocyte migration: combined role of chemokines and extracellular matrix

Abstract

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 microenv...

Triiodothyronine Modulates Thymocyte Migration

“…Fully mature single positive cells are exported from the thymus through blood vessels in the cortico-medullary junction. The mechanisms governing such an exit remain poorly understood, although chemokines and ECM seem to be involved [22][23][24]. After being exported from the thymus, mature T cells colonize the thymusdependent regions of peripheral lymphoid organs and re-circulate before antigen-driven activation.…”

MYB IS Required for B-Selection During Thymopoises

“…As mentioned above, integrin receptor signaling is required for DN3 to DN4 differentiation [301] suggesting that impaired integrin signaling correlates with the phenotype of Myb f/f C and CRT DN3 thymocytes. There is thymocyte developmental stage specific expression of integrins on thymocytes and patterned expression of their ligands, laminin and fibronectin, in the thymus suggesting stage specific functional roles for integrin mediated signaling [127]. Interestingly, in the absence of laminin-2, DN thymocytes are severely reduced in number and undergo apoptosis demonstrating that DN thymocytes require laminin mediated interactions [131].…”

“…DN3 thymocytes express chemokine receptors CXCR4 and CCR9 and cortical thymic epithelial cells express their respective ligands, CXCL12 (SDF-1α) and CCL25 [127]. Thymus specific deletion of CXCR4 resulted in a block beyond DN1 differentiation [34].…”

“…Interestingly, CCR9-deficient DN thymocytes failed to accumulate in the subcapsular zone although their differentiation did not appear to be impaired [128,129]. DN thymocytes also express integrins α4β1 hi , α5β1 hi , α6β1 int [127], α6β4 [130].…”

“…Flow cytometric analysis of DN3 Tcrb-Tg+ thymocytes confirms the microarray analysis prediction of a decrease in Integrin α4 expression. As a positive control we examined expression of β1, which forms heterodimers with the α-integrins, as well as expression of Integrin α6 and α5 which are expressed in DN thymocytes [127].…”