title: Costimulatory Effects of an Immunodominant Parasite Antigen Paradoxically Prevent Induction of Optimal CD8 T Cell Protective Immunity.
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.
authors.affiliation: Department of Internal Medicine, Division of Infectious Diseases, Allergy & Immunology, Saint Louis University Medical Center, St. Louis, Missouri, United States of America.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Eickhoff
authors.affiliation: Department of Internal Medicine, Division of Infectious Diseases, Allergy & Immunology, Saint Louis University Medical Center, St. Louis, Missouri, United States of America.
authors.forename: Xiuli
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Departamento de Biociências, Universidade Federal de São Paulo, Santos, Brazil.
authors.forename: Jose R
authors.initials: JR
authors.lastname: Vasconcelos
authors.affiliation: Department of Internal Medicine, Division of Infectious Diseases, Allergy & Immunology, Saint Louis University Medical Center, St. Louis, Missouri, United States of America.
authors.forename: R Geoffrey
authors.initials: RG
authors.lastname: Motz
authors.affiliation: Department of Internal Medicine, Division of Infectious Diseases, Allergy & Immunology, Saint Louis University Medical Center, St. Louis, Missouri, United States of America.|Department of Molecular Microbiology and Immunology, Saint Louis University Medical Center, St. Louis, Missouri, United States of America.
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Sullivan
authors.affiliation: Department of Internal Medicine, Division of Infectious Diseases, Allergy & Immunology, Saint Louis University Medical Center, St. Louis, Missouri, United States of America.
authors.forename: Kelly
authors.identifier: 0000-0002-8147-4480
authors.initials: K
authors.lastname: O'Shea
authors.affiliation: Department of Biochemistry and Molecular Biology, Saint Louis University Medical Center, St. Louis, Missouri, United States of America.
authors.forename: Nicola
authors.identifier: 0000-0003-2309-7100
authors.initials: N
authors.lastname: Pozzi
authors.affiliation: Department of Biochemistry and Molecular Biology, Saint Louis University Medical Center, St. Louis, Missouri, United States of America.
authors.forename: David W
authors.initials: DW
authors.lastname: Gohara
authors.affiliation: Department of Internal Medicine, Division of Infectious Diseases, Allergy & Immunology, Saint Louis University Medical Center, St. Louis, Missouri, United States of America.|Department of Molecular Microbiology and Immunology, Saint Louis University Medical Center, St. Louis, Missouri, United States of America.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Blase
authors.affiliation: Department of Biochemistry and Molecular Biology, Saint Louis University Medical Center, St. Louis, Missouri, United States of America.
authors.forename: Enrico
authors.initials: E
authors.lastname: Di Cera
authors.affiliation: Department of Internal Medicine, Division of Infectious Diseases, Allergy & Immunology, Saint Louis University Medical Center, St. Louis, Missouri, United States of America.|Department of Molecular Microbiology and Immunology, Saint Louis University Medical Center, St. Louis, Missouri, United States of America.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Hoft
mesh_terms: D000818:Animals; D000953:Antigens, Protozoan / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D014355:Chagas Disease / Q000276:immunology* / Q000469:parasitology / Q000517:prevention & control; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D006023:Glycoproteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007109:Immunity; D016056:Immunodominant Epitopes / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009439:Neuraminidase / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D016052:Protozoan Vaccines / Q000276:immunology*; D014349:Trypanosoma cruzi / Q000276:immunology*; D019444:Vaccines, DNA / Q000276:immunology
chemical_list: D000953:Antigens, Protozoan; D018984:Epitopes, T-Lymphocyte; D006023:Glycoproteins; D016056:Immunodominant Epitopes; D016052:Protozoan Vaccines; D019444:Vaccines, DNA; C069715:trans-sialidase; D009439:Neuraminidase