Abstract
MHC class Ia-restricted CD8+ T cells are important mediators of the adaptive immune response against infections caused by intracellular microorganisms. Whereas antigen-specific effector CD8+ T cells can clear infection caused by intracellular pathogens, in some circumstances, the immune response is suboptimal and the microorganisms survive, causing host death or chronic infection. Here, we explored the cellular and molecular mechanisms that could explain why CD8+ T cell-mediated immunity during infection with the human protozoan parasite Trypanosoma cruzi is not optimal. For that purpose, we compared the CD8+ T-cell mediated immune responses in mice infected with T. cruzi or vaccinated with a recombinant adenovirus expressing an immunodominant parasite antigen. Several functional and phenotypic characteristics of specific CD8+ T cells overlapped. Among few exceptions was an accelerated expansion of the immune response in adenoviral vaccinated mice when compared to infected ones. Also, there was an upregulated expression of the apoptotic-signaling receptor CD95 on the surface of specific T cells from infected mice, which was not observed in the case of adenoviral-vaccinated mice. Most importantly, adenoviral vaccine provided at the time of infection significantly reduced the upregulation of CD95 expression and the proapoptotic phenotype of pathogen-specific CD8+ cells expanded during infection. In parallel, infected adenovirus-vaccinated mice had a stronger CD8 T-cell mediated immune response and survived an otherwise lethal infection. We concluded that a suboptimal CD8+ T-cell response is associated with an upregulation of CD95 expression and a proapoptotic phenotype. Both can be blocked by adenoviral vaccination.
Highlights
The digenetic intracellular protozoan parasite Trypanosoma cruzi (T. cruzi) is the etiologic agent of Chagas’ disease, an acute and chronic illness affecting millions of individual in the Americas [1]
Our observation indicates that CD95 expression by suboptimal CD8+ T cells during infection may be one of the key factors leading to an early increase in apoptosis and a reduced immune response
We investigated the cellular and molecular mechanisms that may account for the suboptimal immunity of specific CD8+ T cells generated during infection with T. cruzi in mice
Summary
The digenetic intracellular protozoan parasite Trypanosoma cruzi (T. cruzi) is the etiologic agent of Chagas’ disease, an acute and chronic illness affecting millions of individual in the Americas [1]. These specific CD8+ T cells are critical for survival following infection, even when limited numbers of parasites initiate infection [2,8]. Despite the CD8+ T cell-mediated immune response, T. cruzi usually survives and establishes a life-long chronic infection. Parasite persistence is an important element of chronic-phase pathologies that occur many years or even decades after initial infection [9,10,11,12,13,14,15]. In any circumstance, the CD8+ T cell-mediated immune response completely eliminate the parasite. The reason for this ineffective or suboptimal immune response is not fully understood. Several potentially significant mechanisms have been described for parasite evasion of the immune response and may account for short- and long-term parasite survival [16]
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