We describe herein the expression of the VLA6 complex by murine thymic epithelial cells (TEC). The immunohistochemical distribution revealed that VLA6 is found in both thymic medullary and ...subcapsullary areas. Moreover, studies by immunoelectron microscopy revealed a membrane labeling of the VLA6 molecule, including at desmosomal sites. By means of immunoblotting, immunoprecipitation, and affinity chromatography of extracts from a mouse TEC line, we further demonstrated that VLA6 is a laminin (LN) receptor in these cells. In keeping with this finding, we showed that TEC adhesion, spreading, and proliferation were enhanced in vitro by LN. The fact that VLA6 is also expressed by the large majority of thymocytes raised the hypothesis that it might be involved in LN-mediated TEC-thymocyte interactions. Interestingly, in vitro experiments showed that there is an increase in the TEC-thymocyte adhesion upon glucocorticoid hormone treatment, a situation in which the expression of VLA6 as well as LN is enhanced. Most importantly, this adhesion can be reversed by pre-treating TEC with an anti-alpha 6 integrin mAb. Additionally, spontaneous in vitro thymocyte release by thymic nurse cell complexes was enhanced by LN and partially blocked by anti-alpha 6 or anti-beta 1 antibodies. Our results suggest that VLA6 is involved in LN-mediated TEC-thymocyte interactions that can be relevant for thymic microenvironmental cell physiology and intrathymic T cell differentiation events.
In Chagas disease, during the acute phase, the establishment of
inflammatory processes is crucial for Trypanosoma cruzi control in
target tissues and for the establishment of host/parasite ...equilibrium.
However, in about 30% of the patients, inflammation becomes
progressive, resulting in chronic disease, mainly characterized by
myocarditis. Although several hypothesis have been raised to explain
the pathogenesis of chagasic myocardiopathy, including the persistence
of the parasite and/or participation of autoimmune processes, the
molecular mechanisms underlying the establishment of the inflammatory
process leading to parasitism control but also contributing to the
maintenance of T. cruzi-elicited chronic myocarditis remain unsolved.
Trying to shed light on these questions, we have for several years been
working with murine models for Chagas disease that reproduce the acute
self-resolving meningoencephalitis, the encephalitis resulting of
reactivation described in immunodeficient individuals, and several
aspects of the acute and chronic myocarditis. In the present review,
our results are summarized and discussed under the light of the current
literature. Furthermore, rational therapeutic intervention strategies
based on integrin-mediated adhesion and chemokine receptor-driven
recruitment of leukocytes are proposed to control T. cruzi-elicited
unbalanced inflammation.
We studied the effects of recombinant interferon-gamma (IFN-gamma) on some aspects of the physiology of two murine thymic epithelial cell (TEC) lines. Besides the expected induction of MHC class II ...antigens, this lymphokine was able to modulate the extracellular matrix (ECM) expression by growing TEC, as well as modulate their adhesion and proliferation patterns. As regards the influence of rIFN-gamma on ECM expression, we observed that when applied in very low doses, it promoted an increase in the amounts of basement membrane proteins, mainly fibronectin. In contrast, relatively high doses of this lymphokine (10(1) to 10(2) IU/ml) induced the opposite effect. Interestingly, both the stimulatory and the blocking effects of IFN-gamma on ECM expression were paralleled by equivalent modulation of cell proliferation, in both mouse and rat TEC lines. It should be pointed out that all these effects could be significantly abrogated by an anti-IFN-gamma monoclonal antibody. Searching for a putative mechanism that could be involved in the modulation of TEC proliferation by IFN-gamma, we observed a clear-cut positive correlation between cell adhesion and proliferation of TEC growing onto ECM-containing substrata produced following IFN-gamma treatment. The bulk of the data presented herein suggests that IFN-gamma may play a relevant role in TEC physiology and ontogeny, not only by inducing MHC class II antigen expression but also by regulating TEC growth via the control of extracellular matrix production by these cells.
The participation of cell adhesion molecules (CAMs) in the
establishment of autoimmune and infectious myocarditis is an important
matter of investigation and may have therapeutic implication.
...Trypanosoma cruzi infection induces a CD8-mediated myocarditis in
patients with severe cardiomyopathy and experimental animals.
Previously, we have proposed that this predominance of CD8+ T-cells is,
at least in part, consequence of the differential expression of CAMs on
circulating CD8+ lymphocytes. In the present study we investigated the
participation of CAMs in shaping the phenotypic nature of the
autoimmune CD4-mediated myosin-induced and the CD8-mediated T.
cruzi-elicited myocarditis. We provide evidence that the prevalence of
a certain T-cell subset inside the inflamed heart reflects the
differential profile of the adhesion molecules VLA-4, LFA-1, and ICAM-1
displayed on a large proportion of this particular T-cell population in
peripheral blood during the early phase of inflammation. Further, the
expression of VCAM-1, ligand for VLA-4, and ICAM-1, counter-receptor
for LFA-1, was up-regulated on vascular endothelium and paralleled the
entrance of inflammatory cells into the cardiac tissue. Thus, this
up-regulated expression of receptors-counter-receptors that regulate
T-cell transmigration through the vascular endothelium may have an
important role in the pathogenesis of the early phase of both
autoimmune and infectious myocarditis.
Intrathymic T-cell migration and differentiation is not completely understood. Here, Wilson Savino and colleagues argue that certain interactions between differentiating thymocytes and thymic ...epithelial cells are mediated by extracellular matrix proteins and that these interactions influence intrathymic migration events and thymocyte differentiation.
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