Abstract
Although CD4+ Foxp3+ T cells are largely described in the regulation of CD4+ T cell responses, their role in the suppression of CD8+ T cell priming is much less clear. Because the induction of CD8+ T cells during experimental infection with Trypanosoma cruzi is remarkably delayed and suboptimal, we raised the hypothesis that this protozoan parasite actively induces the regulation of CD8+ T cell priming. Using an in vivo assay that eliminated multiple variables associated with antigen processing and dendritic cell activation, we found that injection of bone marrow-derived dendritic cells exposed to T. cruzi induced regulatory CD4+ Foxp3+ T cells that suppressed the priming of transgenic CD8+ T cells by peptide-loaded BMDC. This newly described suppressive effect on CD8+ T cell priming was independent of IL-10, but partially dependent on CTLA-4 and TGF-β. Accordingly, depletion of Foxp3+ cells in mice infected with T. cruzi enhanced the response of epitope-specific CD8+ T cells. Altogether, our data uncover a mechanism by which T. cruzi suppresses CD8+ T cell responses, an event related to the establishment of chronic infections.
Highlights
Mouse models of self-curing infections with lymphocytic choriomeningitis virus (LCMV) and Listeria monocytogenes enable CD8+ T cells to be rapidly activated, proliferate and peak between 5 to 10 days post-infection
To investigate whether bone marrow-derived dendritic cells (BMDC) exposure to T. cruzi could affect their ability to prime specific CD8+ T cells, we set up an experimental model using the peptide SIINFEKL (MHC I-restricted epitope from ovalbumin) as antigen and cognate transgenic CD8+ T cells (OTI cells) as responder cells
BMDC were in vitro-exposed to T. cruzi 24 h before LPS stimulation and SIINFEKL peptide loading
Summary
Mouse models of self-curing infections with lymphocytic choriomeningitis virus (LCMV) and Listeria monocytogenes enable CD8+ T cells to be rapidly activated, proliferate and peak between 5 to 10 days post-infection. These lymphocytes differentiate into effector cells and participate in pathogen control and clearance [1,2,3,4,5,6]. Understanding the mechanisms underlying the delayed onset of CD8+ T cell responses in these cases entail the development of interventions to restrain infection. On the other hand, coopting viruses as genetic vectors to induce faster and long-lasting CD8+ T cell responses against T. cruzi has been shown feasible in either prophylactic or therapeutic vaccination protocols [16,17,18]
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