Antigens of Trypanosoma cruzi: an ALLER-RETOUR journey from dendritic cells… to dendritic cells !

Trypanosoma cruzi, the causative agent of Chagas disease, remains a major public health challenge with no effective vaccine. Understanding how dendritic cells (DCs) orchestrate T cell responses is critical to developing new immunotherapeutic strategies. Using a conditional knockout mouse model (Sec22b⁻/⁻ in DCs), we demonstrate that cross-presentation is essential for protective CD8⁺ T cell responses against T. cruzi. Sec22b-deficient mice exhibit increased parasitemia, reduced survival, and impaired CD8⁺ T cell priming. We performed immunopeptidomics on DCs exposed to infected cells or dead parasites, identifying ~20 T. cruzi-derived MHC I peptides per condition, including known antigens like trans-sialidases and flagellin. Vaccination with peptide-pulsed, Poly(I:C)-stimulated BMDCs or with peptide-antibody conjugates targeting Clec9a⁺ DCs led to robust T cell responses and partial protection in vivo. Together, these findings support the critical role of cross-presentation in T. cruzi immunity and highlight the potential of DC-targeted vaccines for Chagas disease.