TNF-α Is Involved in the Abnormal Thymocyte Migration during Experimental Trypanosoma cruzi Infection and Favors the Export of Immature Cells

Abstract

Migratory activity of thymocytes and mature T cell activity seem to be finely tuned by cytokines, chemokines and extracellular matrix components. Previous studies revealed a significant production of inflammatory cytokines together with severe thymic atrophy and thymocyte migratory disturbances during experimental infection with Trypanosoma cruzi, the causative agent of Chagas disease. TNF-alpha production is enhanced during infection and appears to be crucial in the response to the parasite. However, it also seems to play a role in disease pathology, since it is involved in the arrival of T cells to effector sites, including the myocardium. Herein, we analyzed the role of TNF-alpha in the migratory activity of thymocytes in T. cruzi acutely-infected mice. We found increased expression and deposition of TNF-alpha in the thymus of infected animals compared to controls. This was accompanied by increased co-localization of this cytokine with fibronectin, a cell migration-related extracellular matrix molecule, whose contents in the thymus of infected mice is also augmented. In vivo studies showed an enhanced export of thymocytes in T. cruzi-infected mice, as ascertained by intrathymic injection of FITC alone or in combination with TNF-alpha. The Increase in absolute and relative numbers of immature CD4+CD8+ T cells in secondary lymphoid organs were even more clear-cut when TNF-alpha was co-injected with FITC. Ex-vivo transmigration assays also revealed higher number of migrating cells when TNF-alpha was added onto fibronectin lattices, with higher input of all thymocyte subsets, including immature CD4+CD8+ and CD4-CD8- cells. Our findings suggest that in T. cruzi acute infection, when TNF-alpha is complexed with fibronectin, it favours the altered migration of thymocytes, promoting the release of mature and immature T cells to different compartments of the immune system. Conceptually, this work reinforces the notion that thymocyte migration is a multivectorial biological event in health and disease, and that TNF-alpha is a further player in the process.