title: CD4+ T cells are not required for the induction of dengue virus-specific CD8+ T cell or antibody responses but contribute to protection after vaccination.
abstract: The contribution of T cells to the host response to dengue virus (DENV) infection is not well understood. We previously demonstrated a protective role for CD8(+) T cells during primary DENV infection using a mouse-passaged DENV strain and IFN-α/βR(-/-) C57BL/6 mice, which are susceptible to DENV infection. In this study, we examine the role of CD4(+) T cells during primary DENV infection. Four I-A(b)-restricted epitopes derived from three of the nonstructural DENV proteins were identified. CD4(+) T cells expanded and were activated after DENV infection, with peak activation occurring on day 7. The DENV-specific CD4(+) T cells expressed intracellular IFN-γ, TNF, IL-2, and CD40L, and killed peptide-pulsed target cells in vivo. Surprisingly, depletion of CD4(+) T cells before DENV infection had no effect on viral loads. Consistent with this observation, CD4(+) T cell depletion did not affect the DENV-specific IgG or IgM Ab titers or their neutralizing activity, or the DENV-specific CD8(+) T cell response. However, immunization with the CD4(+) T cell epitopes before infection resulted in significantly lower viral loads. Thus, we conclude that whereas CD4(+) T cells are not required for controlling primary DENV infection, their induction by immunization can contribute to viral clearance. These findings suggest inducing anti-DENV CD4(+) T cell responses by vaccination may be beneficial.
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Yauch
authors.forename: Tyler R
authors.initials: TR
authors.lastname: Prestwood
authors.forename: Monica M
authors.initials: MM
authors.lastname: May
authors.forename: Malika M
authors.initials: MM
authors.lastname: Morar
authors.forename: Raphaël M
authors.initials: RM
authors.lastname: Zellweger
authors.forename: Bjoern
authors.initials: B
authors.lastname: Peters
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sette
authors.forename: Sujan
authors.initials: S
authors.lastname: Shresta
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000097:blood / Q000276:immunology*; D000956:Antigens, Viral / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003715:Dengue / Q000097:blood / Q000276:immunology*; D053059:Dengue Vaccines / Q000276:immunology*; D003716:Dengue Virus / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005434:Flow Cytometry; D007150:Immunohistochemistry; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019562:Viral Load
chemical_list: D000914:Antibodies, Viral; D000956:Antigens, Viral; D053059:Dengue Vaccines; D018984:Epitopes, T-Lymphocyte