RESUMEN
Upon activation, cytotoxic CD8(+) T lymphocytes are desialylated exposing beta-galactose residues in a physiological change that enhances their effector activity and that can be monitored on the basis of increased binding of the lectin peanut agglutinin. Herein, we investigated the impact of sialylation mediated by trans-sialidase, a specific and unique Trypanosoma transglycosylase for sialic acid, on CD8(+) T cell response of mice infected with T. cruzi. Our data demonstrate that T. cruzi uses its trans-sialidase enzyme to resialylate the CD8(+) T cell surface, thereby dampening antigen-specific CD8(+) T cell response that might favor its own persistence in the mammalian host. Binding of the monoclonal antibody S7, which recognizes sialic acid-containing epitopes on the 115-kDa isoform of CD43, was augmented on CD8(+) T cells from ST3Gal-I-deficient infected mice, indicating that CD43 is one sialic acid acceptor for trans-sialidase activity on the CD8(+) T cell surface. The cytotoxic activity of antigen-experienced CD8(+) T cells against the immunodominant trans-sialidase synthetic peptide IYNVGQVSI was decreased following active trans-sialidase-mediated resialylation in vitro and in vivo. Inhibition of the parasite's native trans-sialidase activity during infection strongly decreased CD8(+) T cell sialylation, reverting it to the glycosylation status expected in the absence of parasite manipulation increasing mouse survival. Taken together, these results demonstrate, for the first time, that T. cruzi subverts sialylation to attenuate CD8(+) T cell interactions with peptide-major histocompatibility complex class I complexes. CD8(+) T cell resialylation may represent a sophisticated strategy to ensure lifetime host parasitism.
Asunto(s)
Antígenos de Protozoos/metabolismo , Linfocitos T CD8-positivos/metabolismo , Ácido N-Acetilneuramínico/metabolismo , Neuraminidasa/metabolismo , Péptidos/metabolismo , Proteínas Protozoarias/metabolismo , Trypanosoma cruzi/enzimología , Animales , Anticuerpos Monoclonales/inmunología , Antígenos de Protozoos/genética , Antígenos de Protozoos/inmunología , Linfocitos T CD8-positivos/inmunología , Enfermedad de Chagas/enzimología , Enfermedad de Chagas/genética , Enfermedad de Chagas/inmunología , Epítopos/genética , Epítopos/inmunología , Epítopos/metabolismo , Glicosilación , Antígenos de Histocompatibilidad Clase I/genética , Antígenos de Histocompatibilidad Clase I/inmunología , Antígenos de Histocompatibilidad Clase I/metabolismo , Leucosialina/genética , Leucosialina/inmunología , Leucosialina/metabolismo , Activación de Linfocitos/genética , Activación de Linfocitos/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Ácido N-Acetilneuramínico/genética , Ácido N-Acetilneuramínico/inmunología , Neuraminidasa/inmunología , Péptidos/genética , Péptidos/inmunología , Proteínas Protozoarias/genética , Proteínas Protozoarias/inmunología , Sialiltransferasas/genética , Sialiltransferasas/inmunología , Sialiltransferasas/metabolismo , Trypanosoma cruzi/genética , Trypanosoma cruzi/inmunología , beta-Galactosida alfa-2,3-SialiltransferasaRESUMEN
The immunogenicity of sticholysin II (St II), a pore-forming polypeptide from the sea anemone Stichodactyla helianthus, was studied in rabbits using two adjuvants, Freund's and aluminium hydroxide. High titres of antibodies were raised against St II with Freund's adjuvant (FA). The structural homology between sticholysins I and II was also revealed by cross-reactivity assays. Since the oil constituent of FA neutralized the St II haemolytic activity, immunizations with St II-Freund's emulsions were carried out with the inactivated cytolysin. Purified anti-St II IgG also neutralized the St II haemolytic activity.