title: A new TLR2 agonist promotes cross-presentation by mouse and human antigen presenting cells.
abstract: Cross-presentation is the process by which professional APCs load peptides from an extracellularly derived protein onto class I MHC molecules to trigger a CD8(+) T cell response. The ability to enhance this process is therefore relevant for the development of antitumor and antiviral vaccines. We investigated a new TLR2-based adjuvant, Small Molecule Immune Potentiator (SMIP) 2.1, for its ability to stimulate cross-presentation. Using OVA as model antigen, we demonstrated that a SMIP2.1-adjuvanted vaccine formulation induced a greater CD8(+) T cell response, in terms of proliferation, cytokine production and cytolytic activity, than a non-adjuvanted vaccine. Moreover, using an OVA-expressing tumor model, we showed that the CTLs induced by the SMIP2.1 formulated vaccine inhibits tumor growth in vivo. Using a BCR transgenic mouse model we found that B cells could cross-present the OVA antigen when stimulated with SMIP2.1. We also used a flow cytometry assay to detect activation of human CD8(+) T cells isolated from human PBMCs of cytomegalovirus-seropositive donors. Stimulation with SMIP2.1 increased the capacity of human APCs, pulsed in vitro with the pp65 CMV protein, to activate CMV-specific CD8(+) T cells. Therefore, vaccination with an exogenous antigen formulated with SMIP2.1 is a successful strategy for the induction of a cytotoxic T cell response along with antibody production.
authors.affiliation: a Novartis Vaccines and Diagnostics s.r.l. (a GlaxoSmithKline Company) ; Siena , Italy.
authors.forename: Melissa
authors.initials: M
authors.lastname: Santone
authors.forename: Susanna
authors.initials: S
authors.lastname: Aprea
authors.forename: Tom Y H
authors.initials: TY
authors.lastname: Wu
authors.forename: Michael P
authors.initials: MP
authors.lastname: Cooke
authors.forename: M Lamine
authors.initials: ML
authors.lastname: Mbow
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Valiante
authors.forename: James S
authors.initials: JS
authors.lastname: Rush
authors.forename: Stephanie
authors.initials: S
authors.lastname: Dougan
authors.forename: Ana
authors.initials: A
authors.lastname: Avalos
authors.forename: Hidde
authors.initials: H
authors.lastname: Ploegh
authors.forename: Ennio
authors.initials: E
authors.lastname: De Gregorio
authors.forename: Cecilia
authors.initials: C
authors.lastname: Buonsanti
authors.forename: Ugo
authors.initials: U
authors.lastname: D'Oro
mesh_terms: D000276:Adjuvants, Immunologic / Q000378:metabolism*; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology; D049109:Cell Proliferation; D045142:Cross-Priming; D016207:Cytokines / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D005260:Female; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000628:therapy; D010047:Ovalbumin / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000819:agonists*
chemical_list: D000276:Adjuvants, Immunologic; D019496:Cancer Vaccines; D016207:Cytokines; C495342:TLR2 protein, human; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D010047:Ovalbumin
keywords: APC, antigen presenting cell; B cells; BCR, B cell receptor; CMV, cytomegalovirus; CTL, cytotoxic t lymphocyte; DC, dendritic cell; HCMV, human CMV; KO, knock out; LN, lymph node; MHC, major histocompatibility complex; OVA, avalbumin; PBMC, peripheral blood mononuclear cell; SMIP, Small Molecule Immune Potentiator; TLR, toll like receptor; cross presentation/priming; cytotoxic T cells; dendritic cells; vaccination