Trypanosoma cruzi Experimental Infection Impacts on the Thymic Regulatory T Cell Compartment

Abstract

The dynamics of regulatory T cells in the course of Trypanosoma cruzi infection is still debated. We previously demonstrated that acute murine T. cruzi infection results in an impaired peripheral CD4+Foxp3+ T cell differentiation due to the acquisition of an abnormal Th1-like phenotype and altered functional features, negatively impacting on the course of infection. Moreover, T. cruzi infection induces an intense thymic atrophy. As known, the thymus is the primary lymphoid organ in which thymic-derived regulatory T cells, known as tTregs, differentiate. Considering the lack of available data about the effect of T. cruzi infection upon tTregs, we examined tTreg dynamics during the course of disease. We confirmed that T. cruzi infection induces a marked loss of tTreg cell number associated to cell precursor exhaustion, partially avoided by glucocorticoid ablation- and IL-2 survival factor depletion. At the same time, tTregs accumulate within the CD4 single-positive compartment, exhibiting an increased Ki-67/Annexin V ratio compared to controls. Moreover, tTregs enhance after the infection the expression of signature markers (CD25, CD62L and GITR) and they also display alterations in the expression of migration-associated molecules (α chains of VLAs and chemokine receptors) such as functional fibronectin-driven migratory disturbance. Taken together, we provide data demonstrating profound alterations in tTreg compartment during acute murine T. cruzi infection, denoting that their homeostasis is significantly affected. The evident loss of tTreg cell number may compromise the composition of tTreg peripheral pool, and such sustained alteration over time may be partially related to the immune dysregulation observed in the chronic phase of the disease.

Acute Thymic Involution and Mechanisms for Recovery

“…This study demonstrated a significant increase in number of cells positive for the transcriptional factor Foxp3 in the CD4 SP compartment during the acute infection. In contrast, architectural restoration of the thymus and an increase in the number of tTreg cells were observed during the course of chronic infection (González et al 2016). Severe ATI was observed to be a primary event along with an overall 80% loss of DP T cells on the 14th day after experimental infection to induce Chagas disease.…”

“…Increasing prolactin secretion as induced by the administration of metoclopramide, a D2-dopaminergic antagonistic drug 2. Treatment with fingolimod (FTY720), an antagonist of S1P receptor González et al 2016;Lepletier et al 2012Lepletier et al , 2013Lepletier et al , 2014Pérez et al 2012 Plasmodium berghei, P. yoelii and P. berghei ANKA 1. Matrix metalloproteinases (MMPs), i.e., MMP-2 and MMP-9…”

T cell thymic selection and peripheral homeostatic proliferation in infectious diseases

“…Данные молекулы отвечают как за миграцию клеток в тимус, так и за индукцию Treg на периферии. Показано, что стимуляция TLR на ДК продуктами микробного происхождения подавляет экспрессию указанных молекул и, следовательно, ингибирует их миграцию в тимус и снижает их способность индуцировать супрессорные клетки [15,17]. В принципе, не очень понятна роль данного механизма в развитии инфекционного процесса.…”

The Interleukin-17 (IL-17) puzzle in Chagas disease

“…Trypanosoma cruzi is the causative agent of Chagas' disease, a neglected condition [1] . The parasite is transmitted to humans by infected bugs [2] .…”