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Impaired protein catabolism in Trypanosoma cruzi-infected macrophages: possible involvement in antigen presentation
N Plasman1, J G Guillet, B Vray
1Laboratoire d'Immunologie, Faculté de Médecine, Université Libre de Bruxelles, Belgium.
Abstract:
The effect of Trypanosoma cruzi infection on the ability of mature and immature murine peritoneal macrophage (MPM) subpopulations to catabolize the bacteriophage lambda repressor cI protein (cI) has been investigated. The capacity of infected MPM to present the cI and to stimulate various CD4+, I-Ad- or I-Ed-restricted T-cell hybridomas specific for cI was also assessed. Our results show that the radioiodinated cI uptake and catabolism decreased sharply after infection of MPM with T. cruzi. A cI presentation deficiency appeared in mature and immature MPM infected with T. cruzi trypomastigotes. The ability of infected MPM to bind immunogenic cI (12-26) peptides to the plasma membrane Ia molecules was also altered, especially in immature MPM, as shown with paraformaldehyde prefixed MPM, suggesting that these MPM only have a few functional Ia molecules on their membrane. The reduced capacity of cI presentation to the I-Ed-restricted B26.1 hybridomas by infected MPM subpopulations was comparable to that of the I-Ad-restricted B24.4 and B26.2 T cells. The percentage of major histocompatibility complex (MHC) class II-positive MPM was also reduced after T. cruzi infection. The percentage of positive interleukin-2 receptor (IL-2R) MPM was sharply lowered in infected cells, even with a pre- or a post-interferon-gamma (IFN-gamma) activation. Finally, inhibition of prostaglandin with indomethacin, or of nitric oxide with N-monomethyl-L-arginine, or of tumour necrosis factor-alpha (TNF-alpha) with specific monoclonal antibodies did not restore the cI presentation capacities of the MPM subpopulations. Taken together, these results suggest that T. cruzi infection induces a reduced capacity for macrophages to take up and catabolize antigen, resulting in a deficient antigen processing and presentation of the derived immunogenic peptides to specific CD4+ T-helper type-1 cell hybridomas. The decreased cI presenting capacity was a function of the cell's burden and maturity.
Insights
Trypanosoma cruzi infection impairs macrophage antigen processing and presentation. Infected macrophages show reduced uptake, catabolism, and presentation of bacteriophage lambda repressor cI protein to T cells.
Area of Science:
- Immunology
- Parasitology
- Cell Biology
Background:
- Trypanosoma cruzi (T. cruzi) is a parasite that causes Chagas disease.
- Macrophages play a crucial role in the immune response by presenting antigens to T cells.
Purpose of the Study:
- To investigate the effect of T. cruzi infection on murine peritoneal macrophage (MPM) subpopulations.
- To assess the capacity of infected MPM to catabolize and present the bacteriophage lambda repressor cI protein (cI).
- To evaluate the stimulation of T-cell hybridomas by infected MPM presenting cI.
Main Methods:
- Infection of mature and immature MPM with T. cruzi.
- Measurement of radioiodinated cI uptake and catabolism.
- Assessment of cI presentation using T-cell hybridomas.
- Analysis of Ia molecule binding and Major Histocompatibility Complex (MHC) class II expression.
- Flow cytometry for Interleukin-2 receptor (IL-2R) expression.
- Inhibition studies using indomethacin, N-monomethyl-L-arginine, and anti-TNF-alpha antibodies.
Main Results:
- T. cruzi infection significantly reduced cI uptake and catabolism in MPM.
- Both mature and immature infected MPM exhibited a deficiency in cI presentation.
- Binding of cI peptides to Ia molecules was altered, particularly in immature MPM.
- MHC class II and IL-2R expression were decreased in infected MPM, even after IFN-gamma activation.
- Inhibition of prostaglandin, nitric oxide, or TNF-alpha did not restore cI presentation.
Conclusions:
- T. cruzi infection impairs macrophage function, leading to reduced antigen uptake, catabolism, and presentation.
- The observed antigen presentation deficiency is dependent on the parasite burden and macrophage maturity.
- This study highlights a mechanism by which T. cruzi evades the adaptive immune response.