Abnormal T cell traffic in Chagas´ disease

SILVA-BARBOSA SD; PEREZ A; MORROT A; BOTTASSO O; SAVINO W

Rosario

Congreso; VIII Congreso Argentino de Protozoología y Enfermedades Parasitarias. Rosario, 2-5 Noviembre de 2008; 2008

Sociedad Argentina de Protozoología

ABNORMAL T CELL TRAFFIC IN CHAGAS DISEASE Silva-Barbosa SD1, Perez AR2, Morrot A1, Bottasso2, Wilson Savino11Laboratory on Thymus Research, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil; 2Institute of Immunology, National University of Rosario, Rosario, Argentina. Along with the progression of Chagas disease, lymphocyte populations undergo a series of changes in their dynamics, including expansion, differentiation, death, and migration.Studying the murine model of acute Chagas disease, we showed that, in addition to the progressive and massive cell death seen in the thymus of acutely-infected animals, the ex-vivo migration patterns of remaining thymocytes were also altered, as ascertained by the higher migratory response to extracellular matrix (ECM), in association or not with chemokines. Accordingly, thymocytes from infected mice exhibited higher membrane levels of the corresponding ECM and chemokine receptors, and we found an increase in the intrathymic contents of ECM and chemokine ligands, such as fibronectin, laminin and CXCL12, respectively. Interestingly, migratory responses to these ligands were particularly enhanced in the CD4+CD8+ thymocyte subset, and this correlated with the abnormal release of thymus-derived CD4+CD8+ cells into peripheral lymphoid organs seen in infected mice. These peripheral CD4+CD8+ lymphocytes also show abnormally high densities of ECM and CXCL12 receptors. Importantly, they seem to have by-passed normal intrathymic negative selection, since part of them express forbidden TCR clones, thus suggesting an autoimmune potential. Moreover, they exhibit an activated phenotype, as ascertained by the high levels of perforin and interferon-g gene expression. In a second vein, we showed that the CD4+ T cell influx into the heart tissue could be prevented by treatment with antibodies able to block laminin or its receptor VLA-6. Taken together, these data indicate that ECM-mediated interactions can regulate the traffic of potentially reactive cells from the thymus to target tissue and participate of pathophysiology of the cardiac injury seen in chronic T. cruzi infection.Lastly, ongoing studies with blood-derived lymphocytes from chagasic patients also point to an abnormal T cell traffic in human Chagas disease, and that may also be related to the cardiomyopathy progression in these subjects. Financial support: Oswaldo Cruz Foundation & CNPq/ProSul (Brasil).