Trypanosoma cruzi down-regulates lipopolysaccharide-induced MHC class I on human dendritic cells and impairs antigen presentation to specific CD8+ T lymphocytes

Abstract

Trypanosoma cruzi, the etiological agent of Chagas' disease, may persist for many years in its mammalian host. This suggests escape from the immune response and particularly a suboptimal CD8 + T cell response, since these cells are involved in infection control. In this report, we show that T. cruzi inhibits the lipopolysaccharide (LPS)-induced up-regulation of MHC class I molecules at the surface of human dendritic cells (DC). To further investigate the functional consequences of this inhibition, a trypomastigote surface antigen-derived peptide (TSA-1 514±522 peptide) was selected for its stable binding to HLA-A*0201 molecules and used to generate a primary T. cruzispeci®c human CD8 + T cell line in vitro. We observed that DC infected with T. cruzi or treated with T. cruzi-conditioned medium (TCM) had a weaker capacity to present this peptide to the speci®c CD8 + T cell line as shown in an IFN-g ELISPOT assay. Interestingly, T. cruzi or TCM also reduced the antigen presentation capacity of DC to CD8 + T cell lines speci®c for the in¯uenza virus M 58±66 or HIV RT 476±484 epitopes. This dysfunction appears to be linked essentially to reduced MHC class I molecule expression since the stimulation of the RT 476±484 peptide-speci®c CD8 + T cell line was shown to depend mainly on the MHC class I±TCR interaction and not on the co-stimulatory signals which, however, were also inhibited by T. cruzi. This impairment of DC function may represent a novel mechanism reducing in vivo the host's ability to combat ef®ciently T. cruzi infection.

Transfection ofTrypanosoma cruziwith Host CD40 Ligand Results in Improved Control of Parasite Infection

“…T. cruzi trypomastigotes (Y strain) were maintained by weekly intraperitoneal inoculation into male BALB/c mice (6 to 8 weeks old; Bantin & Kingman Universal, Hull, Humberside, United Kingdom) with 100 blood form trypomastigotes in 0.2 ml of phosphate-buffered saline (PBS) on day 0. For challenge infections, the Tehuantepec strain of T. cruzi was maintained in mice like the Y strain and used as previously described (13,33,52,53,56).…”

Cutting Edge: Small Molecule CD40 Ligand Mimetics Promote Control of Parasitemia and Enhance T Cells Producing IFN-γ during ExperimentalTrypanosoma cruziInfection

“…Trypomastigote lysate was obtained by six freeze/thaw cycles and then adjusted to 20 g/ml (6,7). BALB/c, C57BL/6, and C57BL/6 CD40 knockout mice were inoculated i.v.…”

“…As for many other pathogens, the evolutionary adaptation of T. cruzi allows the parasite to evade the immune system and to induce dramatic immunodeficiency (6,7,10). We have previously reported a depletion of both CD4 ϩ and CD8 ϩ T cells at the peak of infection with T. cruzi that is believed to account for high parasitemia and mortality (7).…”

Phosphoinositide 3-Kinase-Dependent Inhibition of Dendritic Cell Interleukin-12 Production byGiardia lamblia

“…Antigens from T. gondii (7,34) and Schistosoma mansoni (10,24,49) have been shown to suppress production of proinflammatory cytokines such as interleukin-12 (IL-12) from TLR-activated antigen-presenting cells. Secreted Trypanosoma cruzi molecules have been shown to activate DCs through TLR4, while infection inhibits DC maturation and responses to lipopolysaccharide (LPS) (44,45). Finally, interactions between dendritic cells and Leishmania spp.…”