title: Definition of Human Epitopes Recognized in Tetanus Toxoid and Development of an Assay Strategy to Detect Ex Vivo Tetanus CD4+ T Cell Responses.
abstract: Despite widespread uses of tetanus toxoid (TT) as a vaccine, model antigen and protein carrier, TT epitopes have been poorly characterized. Herein we defined the human CD4+ T cell epitope repertoire by reevaluation of previously described epitopes and evaluation of those derived from prediction of HLA Class II binding. Forty-seven epitopes were identified following in vitro TT stimulation, with 28 epitopes accounting for 90% of the total response. Despite this diverse range of epitopes, individual responses were associated with only a few immunodominant epitopes, with each donor responding on average to 3 epitopes. For the top 14 epitopes, HLA restriction could be inferred based on HLA typing of the responding donors. HLA binding predictions re-identified the vast majority of known epitopes, and identified 24 additional novel epitopes. With these epitopes, we created a TT epitope pool, which allowed us to characterize TT responses directly ex vivo using a cytokine-independent Activation Induced Marker (AIM) assay. These TT responses were highly Th1 or Th2 polarized, which was dependent upon the original priming vaccine, either the cellular DTwP or acellular DTaP formulation. This polarization remained despite the original priming having occurred decades past and a recent booster immunization with a reduced acellular vaccine formulation. While TT responses following booster vaccination were not durably increased in magnitude, they were associated with a relative expansion of CD4+ effector memory T cells.
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, California, United Ststes of America.
authors.forename: Ricardo
authors.initials: R
authors.lastname: da Silva Antunes
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, California, United Ststes of America.
authors.forename: Sinu
authors.initials: S
authors.lastname: Paul
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, California, United Ststes of America.
authors.forename: John
authors.initials: J
authors.lastname: Sidney
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, California, United Ststes of America.
authors.forename: Daniela
authors.initials: D
authors.lastname: Weiskopf
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, California, United Ststes of America.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Dan
authors.affiliation: Institute for Immunology and Infectious Diseases, Murdoch University, Perth, Western Australia, Australia.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Phillips
authors.affiliation: Institute for Immunology and Infectious Diseases, Murdoch University, Perth, Western Australia, Australia.
authors.forename: Simon
authors.initials: S
authors.lastname: Mallal
authors.affiliation: Institute for Immunology and Infectious Diseases, Murdoch University, Perth, Western Australia, Australia.
authors.forename: Shane
authors.initials: S
authors.lastname: Crotty
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, California, United Ststes of America.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sette
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, California, United Ststes of America.
authors.forename: Cecilia S
authors.initials: CS
authors.lastname: Lindestam Arlehamn
mesh_terms: D000328:Adult; D018604:Epitope Mapping; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000276:immunology*; D005260:Female; D006801:Humans; D007118:Immunoassay; D007156:Immunologic Memory; D008297:Male; D013745:Tetanus Toxoid / Q000737:chemistry / Q000276:immunology*; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology*; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology*
chemical_list: D018984:Epitopes, T-Lymphocyte; D013745:Tetanus Toxoid