Chagasic Thymic Atrophy Does Not Affect Negative Selection but Results in the Export of Activated CD4+CD8+ T Cells in Severe Forms of Human Disease

Abstract

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.

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

“…Previous work strongly indicates that part of these immature cells released from the thymus in T. cruzi infected animals is potentially autoimmune, since they have bypassed the classic intrathymic negative selection [5], [40]. More recently, we showed that such a skewed negative selection is not due to an intrinsic defect of the thymic microenvironmental machinery, since thymic epithelial cell function seems normal in terms of AIRE (autoimmune regulator) and tissues restricted antigen gene expression [27]. Accordingly, it is conceivable that the release of immature cells from the thymus into the periphery is rather a cell migration-related disturbance.…”

“…Such atrophy derives from massive thymocyte depletion, and results in changes in thymocyte export with consequences upon the peripheral T-cell pool and the corresponding T cell repertoire. Previous data strongly indicate that the thymic involution during T. cruzi infection disrupts the homeostasis of the organ, leading to an aberrant output of developing T cells, which likely bypassed intrathymic negative selection events [4], [5], [27], and might be involved in the generation of autoimmunity. Yet, a definitive link between thymic functional abnormalities and the autoimmune events occurring in Chagas disease remains to be demonstrated.…”

“…Importantly, recent data suggest that the occurrence of immature T cells in the periphery of the immune system is extended during chronic phase in both mice and patients infected with T. cruzi [4], [27], [40].…”

Hormonal control of T-cell development in health and disease

“…We have previously shown that the atrophy seen in mice who have acute T. cruzi infection is characterized by a loss of DP thymocytes expressing low levels of TCR, together with an abnormal release of immature thymocytes. 60,123,124 Some of these thymocytes have TCR Vβ families, which under normal conditions should have undergone apoptosis, but persist and might, therefore, lead to an autoimmune reaction. 125 The T. cruzi-induced progressive atrophy of the thymus was paralleled by increased circulating levels of glucocorticoids 126 and could be prevented in mice previously adrenalectomized and treated with the glucocorticoid receptor antagonist, RU486.…”

Dynamics of Lymphocyte Populations duringTrypanosoma cruziInfection: From Thymocyte Depletion to Differential Cell Expansion/Contraction in Peripheral Lymphoid Organs

“…However, regardless of thymic changes promoted by the acute T. cruzi infection, we have showed that the negative selection remains functional [26]. …”