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-γ in response to T cell receptor engagement. The expression of TGF-β 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-β 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-β unresponsiveness failed to restore effector functions of CD8+ T cells isolated from muscle tissue. Histological examination of skeletal muscle from T. cruzi-infected DNRII mice revealed an extensive cellular infiltrate, and DNRII mice displayed higher susceptibility to infection. Overall, while TGF-β 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-β in control of immunopathology in response to T. cruzi infection. © 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.