Abstract
Trypanosoma cruzi infection is controlled but not eliminated by host immunity. The T. cruzi trans-sialidase (TS) gene superfamily encodes immunodominant protective antigens, but expression of altered peptide ligands by different TS genes has been hypothesized to promote immunoevasion. We molecularly defined TS epitopes to determine their importance for protection versus parasite persistence. Peptide-pulsed dendritic cell vaccination experiments demonstrated that one pair of immunodominant CD4+ and CD8+ TS peptides alone can induce protective immunity (100% survival post-lethal parasite challenge). TS DNA vaccines have been shown by us (and others) to protect BALB/c mice against T. cruzi challenge. We generated a new TS vaccine in which the immunodominant TS CD8+ epitope MHC anchoring positions were mutated, rendering the mutant TS vaccine incapable of inducing immunity to the immunodominant CD8 epitope. Immunization of mice with wild type (WT) and mutant TS vaccines demonstrated that vaccines encoding enzymatically active protein and the immunodominant CD8+ T cell epitope enhance subdominant pathogen-specific CD8+ T cell responses. More specifically, CD8+ T cells from WT TS DNA vaccinated mice were responsive to 14 predicted CD8+ TS epitopes, while T cells from mutant TS DNA vaccinated mice were responsive to just one of these 14 predicted TS epitopes. Molecular and structural biology studies revealed that this novel costimulatory mechanism involves CD45 signaling triggered by enzymatically active TS. This enhancing effect on subdominant T cells negatively regulates protective immunity. Using peptide-pulsed DC vaccination experiments, we have shown that vaccines inducing both immunodominant and subdominant epitope responses were significantly less protective than vaccines inducing only immunodominant-specific responses. These results have important implications for T. cruzi vaccine development. Of broader significance, we demonstrate that increasing breadth of T cell epitope responses induced by vaccination is not always advantageous for host immunity.
Highlights
Trypanosoma cruzi is an intracellular protozoan parasite and the causative agent of Chagas disease
Extensive research has been conducted with the goal of broadening vaccine-induced T cell responses, for example to better protect against pathogen immune escape due to epitope mutation
We show that T. cruzi trans-sialidase (TS) induces complex immunodominant and subdominant T cell responses after both T. cruzi infection and TS vaccination
Summary
Trypanosoma cruzi is an intracellular protozoan parasite and the causative agent of Chagas disease. [5,6,7,8,9,10] transfer of T. cruzi-specific CD4+ Th1 cells alone into SCID mice does not provide protection. Adoptive transfer of both naïve CD4+ and naïve CD8+ T cells into SCID mice is absolutely required for reconstitution of immunity against primary T. cruzi challenges. [8] In contrast, activated T. cruzi-specific CD8+ effector T cells alone can transfer protection. [10, 11] Overall, these previous results indicate that CD4+ Th1 cells provide critical helper effects for the development of protective immunity, while CD8+ CTL are required for effector functions protective against T. cruzi infection Adoptive transfer of both naïve CD4+ and naïve CD8+ T cells into SCID mice is absolutely required for reconstitution of immunity against primary T. cruzi challenges. [2] DNA vaccines must encode both CD4+ and CD8+ T. cruzi-specific T cell epitopes to induce protection. [8] In contrast, activated T. cruzi-specific CD8+ effector T cells alone can transfer protection. [10, 11] Overall, these previous results indicate that CD4+ Th1 cells provide critical helper effects for the development of protective immunity, while CD8+ CTL are required for effector functions protective against T. cruzi infection
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