Trypanosoma cruzi infection modulates intrathymic contents of extracellular matrix ligands and receptors and alters thymocyte migration

Abstract

Several T cell abnormalities have been described in the course of acute Trypanosoma cruzi infection in mice, including severe effects on the thymus. In the present study, looking at the expression of extracellular matrix ligands in the thymus, we observed that deposits of fibronectin and laminin increased progressively during the course of infection, reaching a maximum at the peak of parasitemia and thymic atrophy. Concomitantly, membrane expression of fibronectin and laminin receptors (VLA-4, VLA-5 and VLA-6) was also enhanced on thymocyte subsets of infected mice. These results correlated with changes in intrathymic thymocyte migration ability during the acute phase of infection, when a higher fibronectindependent transmigratory activity of CD4 + CD8 + thymocytes was observed. Strikingly, we detected higher frequency of immature and high VLA-expressing CD4 + CD8 + T cells in the peripheral lymphoid organs of infected mice at the peak of parasitemia. These cells seemed to be thymus dependent, since significantly lower amounts of them were found in thymectomized mice, and some of them carry "prohibited" V g segments of the TCR. Our data suggest an imbalance in the intrathymic cell trafficking following acute T. cruzi infection, likely due to dysregulated extracellular matrix-dependent interactions.

Altered Expression of Galectin-3 Induces Cortical Thymocyte Depletion and Premature Exit of Immature Thymocytes during Trypanosoma cruzi Infection

“…32 Moreover, the thymus can be influenced by extrinsic factors such as infections with protozoan parasites, including T. cruzi. [5][6][7][8][9] Acute T. cruzi infection leads to a pronounced depletion of cortical thymocytes and to the escape of a significant number of immature cells to the periphery. 7 The participation of ECM components and chemokines in these phenomena has been suggested.…”

“…7 These immature CD4 ϩ CD8 ϩ T cells are thymus-derived because they were absent in peripheral lymphoid organs of infected thymectomized mice. 7 To investigate if galectin-3 participates in the premature escape of these cells to the periphery, we compared the presence of immature and mature T-cell subsets in the subcutaneous lymph nodes of gal-3 Ϫ/Ϫ and wild-type mice after T. cruzi infection. As expected, an increased number of immature CD4 ϩ CD8 ϩ T cells was observed in the subcutaneous lymph nodes of infected wild-type mice ( Figure 5).…”

“…3,4 We have previously shown that the thymus is severely affected during acute infection with T. cruzi in mice and becomes atrophic because of the death and premature exit of cortical thymocytes. [5][6][7] Moreover, an increased expression of extracellular matrix (ECM) glycoproteins, such as laminin and fibronectin, and their integrin-type receptors occurs during thymic atrophy. 5,7 The cortical population of thymic nurse cells (TNCs), lymphoepithelial complexes in which immature thymocytes undergo differentiation and occasionally die by apoptosis, is altered after infection.…”

“…[5][6][7] Moreover, an increased expression of extracellular matrix (ECM) glycoproteins, such as laminin and fibronectin, and their integrin-type receptors occurs during thymic atrophy. 5,7 The cortical population of thymic nurse cells (TNCs), lymphoepithelial complexes in which immature thymocytes undergo differentiation and occasionally die by apoptosis, is altered after infection. Specifically, in vitro analysis of TNCs recovered from the thymus of infected mice showed that they are smaller in both size and number, have altered expression of ECM molecules, and release thymocytes faster than those from control animals.…”

Cathepsin-L Influences the Expression of Extracellular Matrix in Lymphoid Organs and Plays a Role in the Regulation of Thymic Output and of Peripheral T Cell Number

“…It has also been proposed that thymic ECM glycoproteins would constitute a macromolecular arrangement allowing differentiating thymocytes to migrate (51). Dysregulated ECM production/distribution correlates with alterations in intrathymic cell maturation and trafficking as recently shown in laminin ␣2-chain mutant dy 3k /dy 3k mice (52) and in experimental Chagas' disease (53). In the case of dy 3k /dy 3k mice, the lack of laminin 2 (merosin) is associated with a severe thymic atrophy resulting from apoptosis of double-positive (DP) cells.…”