title: Insights into HLA-restricted T cell responses in a novel mouse model of dengue virus infection point toward new implications for vaccine design.
abstract: The frequency of dengue virus (DENV) infection has increased dramatically in the last few decades, and the lack of a vaccine has led to significant morbidity and mortality worldwide. To date, a convenient murine system to study human T cell responses to DENV has not been available. Mice transgenic for HLA are widely used to model human immune responses, and it has been shown that mouse-passaged DENV is able to replicate to significant levels in IFN-α/βR(-/-) mice. To cover a wide range of HLA phenotypes, we backcrossed IFN-α/βR(-/-) mice with HLA A*0201, A*0101, A*1101, B*0702, and DRB1*0101-transgenic mice. A DENV proteome-wide screen identified a total of 42 epitopes across all HLA-transgenic IFN-α/βR(-/-) strains tested. In contrast, only eight of these elicited responses in the corresponding IFN-α/βR(+/+) mice. We were able to identify T cell epitopes from 9 out of the 10 DENV proteins. However, the majority of responses were derived from the highly conserved nonstructural proteins NS3 and NS5. The relevance of this model is further demonstrated by the fact that most of the epitopes identified in our murine system are also recognized by PBMC from DENV-exposed human donors, and a dominance of HLA B*0702-restricted responses has been detected in both systems. Our results provide new insights into HLA-restricted T cell responses against DENV, and we describe in this study a novel murine model that allows the investigation of T cell-mediated immune mechanisms relevant to vaccine design.
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA
authors.forename: Daniela
authors.initials: D
authors.lastname: Weiskopf
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Yauch
authors.forename: Michael A
authors.initials: MA
authors.lastname: Angelo
authors.forename: Daisy V
authors.initials: DV
authors.lastname: John
authors.forename: Jason A
authors.initials: JA
authors.lastname: Greenbaum
authors.forename: John
authors.initials: J
authors.lastname: Sidney
authors.forename: Ravi V
authors.initials: RV
authors.lastname: Kolla
authors.forename: Aruna D
authors.initials: AD
authors.lastname: De Silva
authors.forename: Aravinda M
authors.initials: AM
authors.lastname: de Silva
authors.forename: Howard
authors.initials: H
authors.lastname: Grey
authors.forename: Bjoern
authors.initials: B
authors.lastname: Peters
authors.forename: Sujan
authors.initials: S
authors.lastname: Shresta
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sette
mesh_terms: D000818:Animals; D053059:Dengue Vaccines / Q000276:immunology*; D004195:Disease Models, Animal; D018604:Epitope Mapping; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D006649:Histocompatibility Antigens / Q000276:immunology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D053059:Dengue Vaccines; D018984:Epitopes, T-Lymphocyte; D006649:Histocompatibility Antigens