Research Article: A Human Trypanosome Suppresses CD8+ T Cell Priming by Dendritic Cells through the Induction of Immune Regulatory CD4+ Foxp3+ T Cells

Date Published: June 22, 2016

Publisher: Public Library of Science

Author(s): Jonatan Ersching, Alexandre Salgado Basso, Vera Lucia Garcia Kalich, Karina Ramalho Bortoluci, Maurício M. Rodrigues, Nisha Jain Garg.


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.

Partial Text

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 [1–6]. Conversely, during experimental mouse infections with Mycobacterium tuberculosis, Salmonella spp, Toxoplasma gondii or Trypanosoma cruzi, the peak of the primary CD8+ T cell immune response occurs only later than 20 days following challenge, in association with host death or the establishment of chronic infections [7–13]. Understanding the mechanisms underlying the delayed onset of CD8+ T cell responses in these cases entail the development of interventions to restrain infection. However, such mechanisms remain ill defined.

Dendritic cells initiate CD8+ T cell-mediated immune responses in different experimental models of infection with viruses, bacteria and protozoans [22–27]. Here, we aimed at clarifying whether exposure to T. cruzi would interfere with antigen presentation function of DC. We observed that T. cruzi exposure drastically impaired the ability of BMDC-SIINFEKL to prime OTI cells in vivo, but not in vitro. Our results greatly diverged from a recent study using a similar approach for OTI CD8+ T cell in vivo priming in the context of LCMV or Listeria monocytogenes infection, where presence of these pathogens did not inhibit and even improved the avidity of cognate OTI cells [28]. These discrepant observations are compatible with the fact that acute infections with these microorganisms elicit a rapid and efficient CD8+ T cell immune response that in most cases cures the host. In contrast, T. cruzi infection elicits a delayed and suboptimal immune response that is unable to protect susceptible mice from death and allows the establishment of a chronic infection in resistant mouse strains [15,16].




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