title: Quality and vaccine efficacy of CD4+ T cell responses directed to dominant and subdominant epitopes in ESAT-6 from Mycobacterium tuberculosis.
abstract: The ESAT-6 (early secretory antigenic target) molecule is a very important target for T cell recognition during infection with Mycobacterium tuberculosis. Although ESAT-6 contains numerous potential T cell epitopes, the immune response during infection is often focused toward a few immunodominant epitopes. By immunization with individual overlapping synthetic peptides in cationic liposomes (cationic adjuvant formulation, CAF01) we demonstrate that the ESAT-6 molecule contains several subdominant epitopes that are not recognized in H-2(d/b) mice either during tuberculosis infection or after immunization with ESAT-6/CAF01. Immunization with a truncated ESAT-6 molecule (Delta15ESAT-6) that lacks the immunodominant ESAT-6(1-15) epitope refocuses the response to include T cells directed to these subdominant epitopes. After aerosol infection of immunized mice, T cells directed to both dominant (ESAT-6-immunized) and subdominant epitopes (Delta15ESAT-6-immunized) proliferate and are recruited to the lung. The vaccine-promoted response consists mainly of double- (TNF-alpha and IL-2) or triple-positive (IFN-gamma, TNF-alpha, and IL-2) polyfunctional T cells. This polyfunctional quality of the CD4(+) T cell response is maintained unchanged even during the later stages of infection, whereas the naturally occurring infection stimulates a response to the ESAT-6(1-15) epitope that consist almost exclusively of CD4(+) effector T cells. ESAT-6 and Delta15ESAT-6 both give significant protection against aerosol challenge with tuberculosis, but the most efficient protection against pulmonary infection is mediated by the subdominant T cell repertoire primed by Delta15ESAT-6.
authors.affiliation: Department of Infectious Immunology, Statens Serum Institute, Copenhagen, Denmark.
authors.forename: Claus Sindbjerg
authors.initials: CS
authors.lastname: Aagaard
authors.forename: Truc Thi Kim Thanh
authors.initials: TT
authors.lastname: Hoang
authors.forename: Carina
authors.initials: C
authors.lastname: Vingsbo-Lundberg
authors.forename: Jes
authors.initials: J
authors.lastname: Dietrich
authors.forename: Peter
authors.initials: P
authors.lastname: Andersen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology* / Q000378:metabolism; D001426:Bacterial Proteins / Q000276:immunology* / Q000378:metabolism / Q000592:standards*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D016056:Immunodominant Epitopes / Q000276:immunology* / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology / Q000592:standards; D014376:Tuberculosis / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D032581:Tuberculosis Vaccines / Q000008:administration & dosage / Q000276:immunology* / Q000592:standards
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; C093276:ESAT-6 protein, Mycobacterium tuberculosis; D016056:Immunodominant Epitopes; D010446:Peptide Fragments; D032581:Tuberculosis Vaccines; D007371:Interferon-gamma