title: The microbial mimic poly IC induces durable and protective CD4+ T cell immunity together with a dendritic cell targeted vaccine.
abstract: CD4(+) Th1 type immunity is implicated in resistance to global infectious diseases. To improve the efficacy of T cell immunity induced by human immunodeficiency virus (HIV) vaccines, we are developing a protein-based approach that directly harnesses the function of dendritic cells (DCs) in intact lymphoid tissues. Vaccine proteins are selectively delivered to DCs by antibodies to DEC-205/CD205, a receptor for antigen presentation. We find that polyriboinosinic:polyribocytidylic acid (poly IC) independently serves as an adjuvant to allow a DC-targeted protein to induce protective CD4(+) T cell responses at a mucosal surface, the airway. After two doses of DEC-targeted, HIV gag p24 along with poly IC, responder CD4(+) T cells have qualitative features that have been correlated with protective function. The T cells simultaneously make IFN-gamma, tumor necrosis factor (TNF)-alpha, and IL-2, and in high amounts for prolonged periods. The T cells also proliferate and continue to secrete IFN-gamma in response to HIV gag p24. The adjuvant role of poly IC requires Toll-like receptor (TLR) 3 and melanoma differentiation-associated gene-5 (MDA5) receptors, but its analog poly IC(12)U requires only TLR3. We suggest that poly IC be tested as an adjuvant with DC-targeted vaccines to induce numerous multifunctional CD4(+) Th1 cells with proliferative capacity.
authors.affiliation: Laboratory of Cellular Physiology and Immunology, Chris Browne Center for Immunology and Immune Diseases, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Trumpfheller
authors.forename: Marina
authors.initials: M
authors.lastname: Caskey
authors.forename: Godwin
authors.initials: G
authors.lastname: Nchinda
authors.forename: Maria Paula
authors.initials: MP
authors.lastname: Longhi
authors.forename: Olga
authors.initials: O
authors.lastname: Mizenina
authors.forename: Yaoxing
authors.initials: Y
authors.lastname: Huang
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Schlesinger
authors.forename: Marco
authors.initials: M
authors.lastname: Colonna
authors.forename: Ralph M
authors.initials: RM
authors.lastname: Steinman
mesh_terms: D000276:Adjuvants, Immunologic; D040761:Biomimetic Materials; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology*; D015683:Gene Products, gag / Q000276:immunology; D006801:Humans; D009092:Mucous Membrane / Q000276:immunology; D011070:Poly I-C / Q000276:immunology*; D051196:Toll-Like Receptor 3 / Q000276:immunology; D014612:Vaccines / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D016207:Cytokines; D015683:Gene Products, gag; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D014612:Vaccines; D011070:Poly I-C