TGF‐β regulates pathology but not tissue CD8⁺ T cell dysfunction during experimental Trypanosoma cruzi infection

Abstract

Infection with the protozoan parasite Trypanosoma cruzi leads to chronic infection, with parasite persistence primarily in muscle tissue. CD8 + T cells isolated from muscle tissue of T. cruzi-infected mice display decreased production of IFN-c in response to T cell receptor engagement. The expression of TGF-b at the site of CD8 + T cell dysfunction and parasite persistence suggested that this immunoregulatory cytokine might play a role in these processes. Mice expressing a T cell-specific dominant negative TGF-b receptor type II (DNRII) were therefore infected with T. cruzi. Infection of DNRII mice resulted in massive CD8 + T cell proliferation, leading to increased numbers but decreased frequencies of antigen-specific CD8 + T cells in the spleen compared to wild-type mice. However, TGF-b unresponsiveness failed to restore effector functions of CD8 + T cells isolated from muscle tissue. Histological examination of skeletal muscle from T. cruziinfected DNRII mice revealed an extensive cellular infiltrate, and DNRII mice displayed higher susceptibility to infection. Overall, while TGF-b does not appear to be responsible for CD8 + T cell unresponsiveness in peripheral tissue in T. cruzi-infected mice, these data suggest a role for TGF-b in control of immunopathology in response to T. cruzi infection.

The TGF-β Pathway as an Emerging Target for Chagas Disease Therapy

“…TGF-β is a pivotal regulator of inflammation during the acute phase of experimental Chagas disease, as shown from the extensive work performed by Silva et al 21 and Gutierrez et al 27 and as reviewed. 20,44 TGF-β is produced during the first week postinfection and constantly throughout the acute and chronic phases in both monkey 45 and mouse 46,47 models. The final outcome depends on multiple factors such as parasite virulence and pathogenicity, coinfection with different T. cruzi clones, and intensity of anti-inflammatory responses induced by T. cruzi molecules via an increase in systemic and local TGF-β levels.…”

Clomipramine and Benznidazole Act Synergistically and Ameliorate the Outcome of Experimental Chagas Disease

“…Photographs were taken using a Nikon Eclipse TE2000-U inverted microscope using a 40ϫ objective. Inflammation was evaluated semiquantitatively on lowpower microscopic examination, according to the distribution and extent of inflammatory cells (focal, confluent, or diffuse) in epicardium and myocardium (1ϩ for a single inflammatory foci, 2ϩ multiple nonconfluent foci of inflammatory infiltrate, 3ϩ for confluent inflammation, and 4ϩ for diffuse inflammation extended throughout the section) (30,31). Furthermore, it also assessed enlarged endothelial cells, perivascular edema, and disrupted and necrotic myocardial fibers.…”

Pharmacological Inhibition of Transforming Growth Factor β Signaling Decreases Infection and Prevents Heart Damage in Acute Chagas' Disease

“…Several studies have demonstrated that TGF-␤ plays a major role in the establishment and pathogenesis of T. cruzi infection (reviewed in reference 2). TGF-␤ plays a crucial role in three important processes associated with Chagas' disease: (i) stimulation of fibrosis, as demonstrated in Chagas' disease patients and experimental animal models (1,31); (ii) parasite cellular invasion and proliferation (10,18,32,34); (iii) downregulation of cellular and immune mechanisms of parasite control (15,27,28). Moreover, significantly higher circulating levels of TGF-␤1 have been observed in patients with Chagas' disease cardiomyopathy (1).…”