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

ANA ROSA PEREZ, LUIZ RICARDO BERBERT, AILIN LEPLETIER DE OLIVEIRA, SILVIA REVELLI, OSCAR BOTTASSO, SUSE DAYSE SILVA-BARBOSA, WILSON SAVINO.

PLOS ONE

PUBLIC LIBRARY SCIENCE

Año: 2012 vol. 22 p. 63814 - 63824

1932-6203

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.