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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-gamma in response to T cell receptor engagement. The expression of TGF-beta 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-beta 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-beta 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-beta 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-beta in control of immunopathology in response to T. cruzi infection.