title: Influence of phthiocerol dimycocerosate on CD4(+) T cell priming and persistence during Mycobacterium tuberculosis infection.
abstract: The characterisation of mycobacterial factors that influence or modulate the host immune response may aid the development of more efficacious TB vaccines. We have previously reported that Mycobacterium tuberculosis deficient in export of Phthiocerol Dimycocerosates (DIM) (MT103(ΔdrrC)) is more attenuated than wild type M. tuberculosis and provides sustained protective immunity compared to the existing BCG vaccine. Here we sought to define the correlates of immunity associated with DIM deficiency by assessing the impact of MT103(ΔdrrC) delivery on antigen presenting cell (APC) function and the generation of CD4(+) T cell antigen-specific immunity. MT103(ΔdrrC) was a potent activator of bone marrow derived dendritic cells, inducing significantly greater expression of CD86 and IL-12p40 compared to BCG or the MT103 parental strain. This translated to an increased ability to initiate early in vivo priming of antigen-specific CD4(+) T cells compared to BCG with enhanced release of IFN-γ and TNF upon antigen-restimulation. The heightened immunity induced by MT103(ΔdrrC) correlated with greater persistence within the spleen compared to BCG, however both MT103(ΔdrrC) and BCG were undetectable in the lung at 70 days post-vaccination. In immunodeficient RAG (-/-) mice, MT103(ΔdrrC) was less virulent than the parental MT103 strain, yet MT103(ΔdrrC) infected mice succumbed more rapidly compared to BCG-infected animals. These results suggest that DIM translocation plays a role in APC stimulation and CD4(+) T cell activation during M. tuberculosis infection and highlights the potential of DIM-deficient strains as novel TB vaccine candidates.
authors.affiliation: Microbial Pathogenesis and Immunity Group, Department of Infectious Diseases and Immunology, University of Sydney, NSW, Australia; Mycobacterial Research Program, Centenary Institute, Newtown, NSW, Australia.
authors.forename: Rachel
authors.initials: R
authors.lastname: Pinto
authors.affiliation: Microbial Pathogenesis and Immunity Group, Department of Infectious Diseases and Immunology, University of Sydney, NSW, Australia; Mycobacterial Research Program, Centenary Institute, Newtown, NSW, Australia.
authors.forename: Jonathan K
authors.initials: JK
authors.lastname: Nambiar
authors.affiliation: Microbial Pathogenesis and Immunity Group, Department of Infectious Diseases and Immunology, University of Sydney, NSW, Australia; Mycobacterial Research Program, Centenary Institute, Newtown, NSW, Australia.
authors.forename: Lisa
authors.initials: L
authors.lastname: Leotta
authors.affiliation: Microbial Pathogenesis and Immunity Group, Department of Infectious Diseases and Immunology, University of Sydney, NSW, Australia; Mycobacterial Research Program, Centenary Institute, Newtown, NSW, Australia.
authors.forename: Claudio
authors.initials: C
authors.lastname: Counoupas
authors.affiliation: Mycobacterial Research Program, Centenary Institute, Newtown, NSW, Australia; Discipline of Medicine, Central Clinical School, Sydney Medical School, University of Sydney, NSW, Australia.
authors.forename: Warwick J
authors.initials: WJ
authors.lastname: Britton
authors.affiliation: Microbial Pathogenesis and Immunity Group, Department of Infectious Diseases and Immunology, University of Sydney, NSW, Australia; Mycobacterial Research Program, Centenary Institute, Newtown, NSW, Australia. Electronic address: jamie.triccas@sydney.edu.au.
authors.forename: James A
authors.initials: JA
authors.lastname: Triccas
mesh_terms: D000818:Animals; D001500:BCG Vaccine / Q000008:administration & dosage / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D004195:Disease Models, Animal; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics; D054884:Host-Pathogen Interactions; D008055:Lipids / Q000276:immunology*; D008213:Lymphocyte Activation; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D014376:Tuberculosis / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000517:prevention & control*; D032581:Tuberculosis Vaccines / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism; D014613:Vaccines, Attenuated / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism; D014774:Virulence
chemical_list: D001500:BCG Vaccine; D018398:Homeodomain Proteins; D008055:Lipids; D011948:Receptors, Antigen, T-Cell; D032581:Tuberculosis Vaccines; D014613:Vaccines, Attenuated; C064658:RAG-1 protein; C008901:phthiocerol dimycocerosate
keywords: CD4 T cell immunity; Mycobacterium tuberculosis; Phthiocerol dimycocerosate; Vaccination; Virulence