Extrathymic CD4+CD8+ double-positive (DP) T cells are increased in some pathophysiological conditions, including
infectious diseases. In the murine model of
Chagas disease, it has been shown that the protozoan parasite Trypanosoma cruzi is able to target the thymus and induce alterations of the thymic microenvironment and the lymphoid compartment. In the acute phase, this results in a severe
atrophy of the organ and early release of DP cells into the periphery. To date, the effect of the changes promoted by the
parasite infection on thymic central tolerance has remained elusive. Herein we show that the intrathymic key elements that are necessary to promote the negative selection of thymocytes undergoing maturation during the thymopoiesis remains functional during the acute chagasic thymic
atrophy. Intrathymic expression of the autoimmune regulator factor (Aire) and tissue-restricted
antigen (TRA) genes is normal. In addition, the expression of the proapoptotic
Bim protein in thymocytes was not changed, revealing that the
parasite infection-induced thymus
atrophy has no effect on these marker genes necessary to promote clonal deletion of T cells. In a chicken egg
ovalbumin (OVA)-specific
T-cell receptor (TCR) transgenic system, the administration of OVA
peptide into infected mice with thymic
atrophy promoted OVA-specific thymocyte apoptosis, further indicating normal negative selection process during the
infection. Yet, although the intrathymic checkpoints necessary for thymic negative selection are present in the acute phase of
Chagas disease, we found that the DP cells released into the periphery acquire an activated phenotype similar to what is described for activated effector or memory single-positive T cells. Most interestingly, we also demonstrate that increased percentages of peripheral blood subset of DP cells exhibiting an activated HLA-DR+ phenotype are associated with severe cardiac forms of human chronic
Chagas disease. These cells may contribute to the immunopathological events seen in the
Chagas disease.