CTLA-4 regulates the murine immune response to Trypanosoma cruzi infection
S. E. B. Graefe,
T. Jacobs,
U. Wächter,
B. M. Bröker,
B. Fleischer,
Corresponding Author
S. E. B. Graefe
Bernhard-Nocht-Institute, Department of Immunology, Hamburg, Germany
S. E. B. Graefe, Bernhard-Nocht-Institute, Department of Immunology, Bernhard-Nocht-St. 74, D-20359 Hamburg, Germany (e-mail: [email protected]).Search for more papers by this authorT. Jacobs
Bernhard-Nocht-Institute, Department of Immunology, Hamburg, Germany
Search for more papers by this authorU. Wächter
Bernhard-Nocht-Institute, Department of Immunology, Hamburg, Germany
Search for more papers by this authorB. M. Bröker
Bernhard-Nocht-Institute, Department of Immunology, Hamburg, Germany
Current address: Department of Immunology, Ernst-Moritz-Arndt-University of Greifswald, Greifswald, Germany
Search for more papers by this authorB. Fleischer
Bernhard-Nocht-Institute, Department of Immunology, Hamburg, Germany
Search for more papers by this authorS. E. B. Graefe,
T. Jacobs,
U. Wächter,
B. M. Bröker,
B. Fleischer,
Corresponding Author
S. E. B. Graefe
Bernhard-Nocht-Institute, Department of Immunology, Hamburg, Germany
S. E. B. Graefe, Bernhard-Nocht-Institute, Department of Immunology, Bernhard-Nocht-St. 74, D-20359 Hamburg, Germany (e-mail: [email protected]).Search for more papers by this authorT. Jacobs
Bernhard-Nocht-Institute, Department of Immunology, Hamburg, Germany
Search for more papers by this authorU. Wächter
Bernhard-Nocht-Institute, Department of Immunology, Hamburg, Germany
Search for more papers by this authorB. M. Bröker
Bernhard-Nocht-Institute, Department of Immunology, Hamburg, Germany
Current address: Department of Immunology, Ernst-Moritz-Arndt-University of Greifswald, Greifswald, Germany
Search for more papers by this authorB. Fleischer
Bernhard-Nocht-Institute, Department of Immunology, Hamburg, Germany
Search for more papers by this authorParts of this publication represent the doctoral thesis of Uta Wächter.
SUMMARY
Infection with Trypanosoma cruzi causes a profound suppression of T cell responsiveness to polyclonal or antigenic stimuli. In this study, we quantified expression of the negative T cell regulatory molecule CTLA-4 in T. cruzi infected mice and analysed its influence on the immune suppression. Levels of splenic CTLA-4 expression were highest around day 10 after infection, reaching 5% in resistant B6D2F1 mice, but exceeding 10% of CD4+ T cells in C57BL/6 mice that were susceptible to mortal disease. The proliferative response of explanted splenocytes to CD3-mediated stimulation was strongly suppressed in both the susceptible and the resistant strains. Blockade of CTLA-4 in vitro with a monoclonal antibody affected neither proliferative response nor cytokine production (IFN-γ, IL-4 and IL-2) by splenic T cells from infected C57BL/6 mice. Treatment of mice with anti-CTLA-4 antibody on the day of infection decreased IFN-γ production and reduced mortality by about 50%. We conclude that high CTLA-4 expression is a hallmark of severe disease in murine T. cruzi infection, and that CTLA-4 has a regulative influence at the early stages during priming of the immune reaction to the parasite, augmenting a strong Th1-biased response.
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