Malnutrition, secondary to deficiency in intake of proteins, minerals or vitamins, consistently results in changes in the thymus. This organ undergoes a severe atrophy due to apoptosis-induced thymocyte depletion, particularly affecting the immature CD4 þ CD8 þ cells, as well as a decrease in cell proliferation. This feature is apparently linked to a hormonal imbalance, involving a decrease in leptin and consequent increase in glucocorticoid hormone levels in the serum. The thymic microenvironment is also affected in malnutrition: morphological changes in thymic epithelial cells have been found, together with a decrease of thymic hormone production by these cells. Additionally, intrathymic contents of extracellular proteins, such as fibronectin, laminin and collagens, are increased in thymuses from malnourished children. Taken together, these data clearly point to the notion that the thymus is significantly affected in malnutrition. Similar patterns of thymic changes occur in acute infectious diseases, including a severe atrophy of the organ, mainly due to the apoptosis-related depletion of immature CD4 þ CD8 þ thymocytes. Additionally, thymocyte proliferation is compromised in acutely-infected subjects. The microenvironmental compartment of the thymus is also affected in acute infections, with an increased density of the epithelial network and an increase in the deposition of extracellular matrix. In conclusion, it seems clear that the thymus is targeted in malnutrition as well as in acute infections. These changes are related to the impaired peripheral immune response seen in malnourished and infected individuals. Thus, strategies inducing thymus replenishment should be considered in therapeutic approaches, in both malnutrition and acute infectious diseases.

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.

No abstract