title: ESAT-6 and HspX improve the effectiveness of BCG to induce human dendritic cells-dependent Th1 and NK cells activation.
abstract: The limited efficacy of the BCG vaccine against tuberculosis is partly due to the missing expression of immunogenic proteins. We analyzed whether the addition to BCG of ESAT-6 and HspX, two Mycobacterium tuberculosis (Mtb) antigens, could enhance its capacity to activate human dendritic cells (DCs). BCG showed a weak ability to induce DC maturation, cytokine release, and CD4(+) lymphocytes and NK cells activation. The addition of ESAT-6 or HspX alone to BCG-stimulated DC did not improve these processes, whereas their simultaneous addition enhanced BCG-dependent DC maturation and cytokine release, as well as the ability of BCG-treated DCs to stimulate IFN-γ release and CD69 expression by CD4(+) lymphocytes and NK cells. Addition of TLR2-blocking antibody decreased IL-12 release by BCG-stimulated DCs incubated with ESAT-6 and HspX, as well as IFN-γ secretion by CD4(+) lymphocytes co-cultured with these cells. Moreover, HspX and ESAT-6 improved the capacity of BCG-treated DCs to induce the expression of memory phenotype marker CD45RO in naïve CD4(+) T cells. Our results indicate that ESAT-6 and HspX cooperation enables BCG-treated human DCs to induce T lymphocyte and NK cell-mediated immune responses through TLR2-dependent IL-12 secretion. Therefore ESAT-6 and HspX represent good candidates for improving the effectiveness of BCG vaccination.
authors.affiliation: Department of Pathology and Diagnostics, Section of General Pathology, University of Verona, Verona, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Marongiu
authors.forename: Marta
authors.initials: M
authors.lastname: Donini
authors.forename: Lara
authors.initials: L
authors.lastname: Toffali
authors.forename: Elena
authors.initials: E
authors.lastname: Zenaro
authors.forename: Stefano
authors.initials: S
authors.lastname: Dusi
mesh_terms: D000942:Antigens, Bacterial / Q000494:pharmacology*; D015703:Antigens, CD / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D001500:BCG Vaccine / Q000276:immunology*; D001426:Bacterial Proteins / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D037181:Lectins, C-Type / Q000378:metabolism; D000099192:CD69 Antigens
chemical_list: D000942:Antigens, Bacterial; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D001500:BCG Vaccine; D001426:Bacterial Proteins; D016207:Cytokines; D007371:Interferon-gamma; D018664:Interleukin-12; D037181:Lectins, C-Type; D000099192:CD69 Antigens; C093276:ESAT-6 protein, Mycobacterium tuberculosis; C118127:HspX protein, Mycobacterium tuberculosis