The Thymus in Chagas Disease: Molecular Interactions Involved in Abnormal T-Cell Migration and Differentiation

Abstract

Chagas disease, caused by the protozoan parasite T. cruzi , is a prevalent parasitic disease in Latin America. Presently, it is spreading around the world by human migration, thus representing a new global health issue. Chronically infected individuals reveal a dissimilar disease progression: while nearly 60% remain without apparent disease for life, 30% develop life-threatening pathologies, such as chronic chagasic cardiomyopathy (CCC) or megaviscerae. Inflammation driven by parasite persistence seems to be involved in the pathophysiology of the disease. However, there is also evidence of the occurrence of autoimmune events, mainly caused by molecular mimicry and bystander activation. In experimental models of disease, is well-established that T. cruzi infects the thymus and causes locally profound structural and functional alterations. The hallmark is a massive loss of CD4 + CD8 + double positive (DP) thymocytes, mainly triggered by increased levels of glucocorticoids, although other mechanisms seem to act simultaneously. Thymic epithelial cells (TEC) exhibited an increase in extracellular matrix deposition, which are related to thymocyte migratory alterations. Moreover, medullary TEC showed a decreased expression of AIRE and altered expression of microRNAs, which might be linked to a disrupted negative selection of the T-cell repertoire. Also, almost all stages of thymocyte development are altered, including an abnormal output of CD4 − CD8 − double negative (DN) and DP immature and mature cells, many of them carrying prohibited TCR-Vβ segments. Evidence has shown that DN and DP cells with an activated phenotype can be tracked in the blood of humans with chronic Chagas disease and also in the secondary lymphoid organs and heart of infected mice, raising new questions about the relevance of these populations in the pathogenesis of Chagas disease and their possible link with thymic alterations and an immunoendocrine imbalance. Here, we discuss diverse molecular mechanisms underlying thymic abnormalities occurring during T. cruzi infection and their link with CCC, which may contribute to the design of innovative strategies to control Chagas disease pathology.

Thymus, undernutrition, and infection: Approaching cellular and molecular interactions

“…Such specific distribution indicates that thymocyte maturation occurs in parallel with organized and coordinated cell migration ( 14 ). In fact, disruption or abnormal cell migration impacts thymocyte development, as seen for example in Chagas disease ( 15 ).…”

“…Intrathymic thymocyte differentiation and migration, from the entrance of precursor cells to the exit of mature SP cells, is dependent on interactions controlled by the thymic tridimensional network. This is composed by cellular components such as thymic epithelial cells (TEC), thymic dendritic cells (TDC), macrophages and fibroblasts, as well as non-soluble and soluble molecules such as the extracellular matrix (ECM) proteins fibronectin, laminin, type I and IV collagens; cytokines as interleukin (IL)-2, IL-6, IL-7, and IL-22; chemokines as CXCL12, CCL4, and CCL7; hormones as thymosin, thymopoietin, and thymulin; and different typical soluble components of nervous tissues, such as neuropeptides and neurotransmitters ( 12 , 15 , 16 ).…”

Does Autoimmunity Play a Role in the Immunopathogenesis of Vasculitis Associated With Chronic Chagas Disease?

“…Furthermore, toxin and bioactive lipids release, microvascular changes, and T cell-mediated delayed-type hypersensitivity, perpetuate the damage and the immune vicious circle ( Leon et al., 2001 ; Engman and Leon, 2002 ; Bonney and Engman, 2015 ). Recently, important local structural and functional alterations have been described as a consequence of thymic infection by T. cruzi , which produces abnormal thymocyte migration and a disrupted negative selection of the T-cell repertoire ( Pérez et al., 2020 ). Secondarily, abnormal activated double-positive and double-negative lymphocytes with a proinflammatory phenotype have been found in patients with CD.…”

Transcriptional Regulation of Early T-Lymphocyte Development in Thymus

“…Subsequently, thymocytes must pass through both positive and negative selections to become mature T cells. Thymocytes with functional TCRs interact with the major histocompatibility complex (MHC) on cortical epithelial cells (cTECs) presenting foreign antigens will survive ( 6 ). Thus, positive selection is vital for MHC restrictions.…”