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Trypanosoma cruzi infection suppresses nuclear factors that bind to specific sites on the interleukin-2 enhancer
1Department of Zoology, University of Georgia, Athens 30602.
Abstract:
Interleukin-2 (IL-2) gene expression, a critical early event during T lymphocyte activation, is severely suppressed in mice infected with the protozoan parasite Trypanosoma cruzi, the causative agent of human Chagas' disease. Our previous observation that reduction of IL-2 mRNA in T cells from T. cruzi-infected mice is not due to an increased degradation of the mRNA suggests a repression of the IL-2 gene at the transcriptional level. In this study, we have measured the level of nuclear factors that bind to specific sites on the IL-2 enhancer. Splenocytes and splenic T cells from acutely infected mice show a marked decrease in the level of AP-1, and a modest decrease in the level of NF-kappa B and nuclear factor of activated T cells (NF-AT). DNA-binding activity of Oct-1 was least affected in T cells from infected mice. Although the basal level of AP-1 activity is comparable in cells from uninfected and infected mice, mitogen-induced AP-1 activation is absent in the cells from T. cruzi-infected mice. Sodium deoxycholate treatment slightly enhances NF-kappa B-binding activity in splenocyte nuclear and whole-cell extracts from infected mice, suggesting that a blockage of the activation of NF-kappa B is only partially responsible for the decrease in the level of NF-kappa B in T cells from T. cruzi-infected mice. These data identify the molecular basis of IL-2 gene regulation in T. cruzi infection and suggest that T cells are anergized as a result of the infection.
Insights
Trypanosoma cruzi infection suppresses Interleukin-2 (IL-2) gene expression by reducing key transcription factors like AP-1 in T cells. This transcriptional repression leads to anergized T cells, impacting immune response to Chagas
Area of Science:
- Immunology
- Molecular Biology
- Parasitology
Background:
- Interleukin-2 (IL-2) gene expression is crucial for T lymphocyte activation.
- Trypanosoma cruzi infection, the cause of Chagas' disease, severely suppresses IL-2 production.
- Previous studies indicated IL-2 mRNA reduction is due to transcriptional repression, not degradation.
Purpose of the Study:
- To investigate the molecular mechanisms of IL-2 gene transcriptional repression in T. cruzi infection.
- To quantify the levels of nuclear factors binding to the IL-2 enhancer in infected T cells.
- To understand the impact of T. cruzi infection on T cell activation and function.
Main Methods:
- Measurement of nuclear factor binding activity to IL-2 enhancer sites.
- Analysis of transcription factors AP-1, NF-kappa B, NF-AT, and Oct-1 in splenocytes and splenic T cells.
- Assessment of mitogen-induced transcription factor activation.
- Evaluation of sodium deoxycholate effects on NF-kappa B binding activity.
Main Results:
- A marked decrease in AP-1 binding activity and a modest decrease in NF-kappa B and NF-AT binding were observed in T cells from infected mice.
- Oct-1 DNA-binding activity was least affected.
- Mitogen-induced AP-1 activation was abolished in T cells from infected mice, while basal AP-1 activity remained comparable.
- Sodium deoxycholate partially enhanced NF-kappa B binding, suggesting incomplete activation blockage.
Conclusions:
- T. cruzi infection molecularly represses IL-2 gene expression at the transcriptional level.
- Reduced binding of transcription factors, particularly AP-1, is a key mechanism.
- These findings suggest T cell anergy as a consequence of T. cruzi infection.