Abstract
Infection with the protozoan parasite Trypanosoma cruzi may lead to a potentially fatal cardiomyopathy known as Chagas heart disease. This disease is characterized by infiltration of the myocardium by mononuclear cells, including CD4+ T cells, together with edema, myofibrillary destruction, and fibrosis. A multifaceted systemic immune response develops that ultimately keeps parasitemia and tissue parasitosis low. T helper 1 and other pro-inflammatory T cell responses are effective at keeping levels of T. cruzi low in tissues and blood, but they may also lead to tissue inflammation when present chronically. The mechanism by which the inflammatory response is regulated in T. cruzi-infected individuals is complex, and the specific roles that Th17 and T regulatory (Treg) cells may play in that regulation are beginning to be elucidated. In this study, we found that depletion of Treg cells in T. cruzi-infected mice leads to reduced cardiac parasitosis and inflammation, accompanied by an augmented Th1 response early in the course of infection. This is followed by a downregulation of the Th1 response and increased Th17 response late in infection. The effect of Treg cell depletion on the Th1 and Th17 cells is not observed in mice immunized with T. cruzi in adjuvant. This suggests that Treg cells specifically regulate Th1 and Th17 cell responses during T. cruzi infection and may also be important for modulating parasite clearance and inflammation in the myocardium of T. cruzi-infected individuals.
Highlights
Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, constitutes a major public health burden in Latin America, and is the leading cause of infectious myocarditis in the world (Kirchhoff et al 2004)
A reduction in the proportion of CD4+ cells that was Foxp3+ was observed in both groups at 10 d.p.i.; by 21 d.p.i. there was an approximately two-fold increase in the percent of CD4+Foxp3+ in T. cruzi-infected mice (Fig. 2B). These data indicate that down-regulation of CD25 expression, which has been demonstrated to be necessary for T regulatory (Treg) function, was maintained throughout the course of this experiment, even though there was an increase in the proportion of CD4+Foxp3+ cells in T. cruzi-infected mice during the course of infection
Treg cells have an important and complex relationship with Th1 and Th17 cells, as Treg cells and Th17 cells develop from naïve CD4+ T cells under the influences of some of the same factors, yet have largely opposing functions, and both modulate the function of Th1 cells during the development of potentially pathogenic inflammatory responses(Le Cabec et al 2005; Xu et al 2007) (Dardalhon et al 2008; Le Cabec et al 2005; Li et al 2007; Speert and Silverstein 1985; Xu et al 2007)
Summary
Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, constitutes a major public health burden in Latin America, and is the leading cause of infectious myocarditis in the world (Kirchhoff et al 2004). The etiology of Chagas disease is multifaceted, and may involve an autoimmune component in addition to protracted damage to myocytes and cardiac neuronal and vascular networks caused by parasites persisting in host tissues (Bonney et al 2011; Cummings and Tarleton 2003; Davila et al 1989; Girones et al 2007; Leon et al 2004; Ribeiro dos Santos et al 1992; Rossi 1990; Teixeira et al 2011; Zhang and Tarleton 1999) Both cytotoxic CD8+ effector T lymphocytes and IFN-γ-producing CD4+ T cells (Th1 cells), are important for controlling T. cruzi parasitosis (Hoft et al 2000; Hunter et al 1997; Kumar and Tarleton 2001; Rodrigues et al 2000; Tzelepis et al 2007), yet these T cells may contribute to the development of pathogenic inflammation during T. cruzi infection (Bonney et al 2011; Gomes et al 2003; Laucella et al 2004; Minoprio 2001; Ribeiro dos Santos et al 1992; Rizzo et al 1989; Rocha Rodrigues et al 2012; Soares et al 2001; Tarleton et al 1996; Tarleton et al 1994).
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