Involvement of CD4⁺Th1 Cells in Systemic Immunity Protective against Primary and Secondary Challenges withTrypanosoma cruzi

Abstract

In general, gamma interferon (IFN-␥)-producing CD4؉ Th1 cells are important for the immunological control of intracellular pathogens. We previously demonstrated an association between parasite-specific induction of IFN-␥ responses and resistance to the intracellular protozoan Trypanosoma cruzi. To investigate a potential causal relationship between Th1 responses and T. cruzi resistance, we studied the ability of Th1 cells to protect susceptible BALB/c mice against virulent parasite challenges. We developed immunization protocols capable of inducing polarized Th1 and Th2 responses in vivo. Induction of parasite-specific Th1 responses, but not Th2 responses, protected BALB/c mice against virulent T. cruzi challenges. We generated T. cruzi-specific CD4 ؉ Th1 and Th2 cell lines from BALB/c mice that were activated by infected macrophages to produce their corresponding cytokine response profiles. Th1 cells, but not Th2 cells, induced nitric oxide production and inhibited intracellular parasite replication in T. cruzi-infected macrophages. Despite the ability to inhibit parasite replication in vitro, Th1 cells alone could not adoptively transfer protection against T. cruzi to SCID mice. In addition, despite the fact that the adoptive transfer of CD4 ؉ T lymphocytes was shown to be necessary for the development of immunity protective against primary T. cruzi infection in our SCID mouse model, protective secondary effector functions could be transferred to SCID mice from memory-immune BALB/c mice in the absence of CD4 ؉ T lymphocytes. These results indicate that, although CD4 ؉ Th1 cells can directly inhibit intracellular parasite replication, a more important role for these cells in T. cruzi systemic immunity may be to provide helper activity for the development of other effector functions protective in vivo.

Antigen-Specific Th1 But Not Th2 Cells Provide Protection from Lethal Trypanosoma cruzi Infection in Mice

“…Using the Th1/Th2 cell transfer system, we demonstrate that initial priming of a Th1 response is required for control of T. cruzi infection. This conclusion is supported by the recent results of Hoft et al (48) demonstrating that immunization of mice under conditions that promote a Th1 response results in protection from challenge infection with T. cruzi. In addition, these results confirm and extend the findings from our laboratory that mice lacking the ability to produce Th2 responses (as a result of targeted knock-of the stat6 gene) develop highly efficient immune responses and less sever disease than wild-type mice (61).…”

Neutrophil depletion exacerbates experimental Chagas' disease in BALB / c, but protects C57BL / 6 mice through modulating the Th1 / Th2 dichotomy in different directions

“…Interestingly, we found that neutrophils play opposite roles in these two strains of mice with respect to protection or exacerbation of T. cruzi infection, possibly through modulating the Th1/Th2 dichotomy in different directions. Our results may add to the understanding of the role of Th1/Th2 dichotomy for pathogenesis of T. cruzi infection, which has been regarded as more complicated than that in L. major infection [3,10].…”

Antigen-Specific T Cells Maintain an Effector Memory Phenotype during Persistent Trypanosoma cruzi Infection

“…Parasite-specific CD4 ϩ T cells inhibit T. cruzi replication in vitro (5) and confer protection against lethal challenge in vivo (6). Induction of T. cruzi-specific CD4 ϩ and CD8 ϩ T cells is a critical component of vaccine-induced immunity to T. cruzi (7)(8)(9).…”