title: Mycobacterium tuberculosis EsxH inhibits ESCRT-dependent CD4+T-cell activation.
abstract: Mycobacterium tuberculosis (Mtb) establishes a persistent infection, despite inducing antigen-specific T-cell responses. Although T cells arrive at the site of infection, they do not provide sterilizing immunity. The molecular basis of how Mtb impairs T-cell function is not clear. Mtb has been reported to block major histocompatibility complex class II (MHC-II) antigen presentation; however, no bacterial effector or host-cell target mediating this effect has been identified. We recently found that Mtb EsxH, which is secreted by the Esx-3 type VII secretion system, directly inhibits the endosomal sorting complex required for transport (ESCRT) machinery. Here, we showed that ESCRT is required for optimal antigen processing; correspondingly, overexpression and loss-of-function studies demonstrated that EsxH inhibited the ability of macrophages and dendritic cells to activate Mtb antigen-specific CD4+T cells. Compared with the wild-type strain, the esxH-deficient strain induced fivefold more antigen-specific CD4+T-cell proliferation in the mediastinal lymph nodes of mice. We also found that EsxH undermined the ability of effector CD4+T cells to recognize infected macrophages and clear Mtb. These results provide a molecular explanation for how Mtb impairs the adaptive immune response.
authors.affiliation: Division of Infectious Diseases, Department of Medicine, New York University School of Medicine, New York, New York 10016, USA.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Portal-Celhay
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.|Center for Microbial Pathogenesis, Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia 30303, USA.
authors.forename: JoAnn M
authors.initials: JM
authors.lastname: Tufariello
authors.affiliation: Division of Infectious Diseases, Department of Medicine, New York University School of Medicine, New York, New York 10016, USA.
authors.forename: Smita
authors.initials: S
authors.lastname: Srivastava
authors.affiliation: Division of Infectious Diseases, Department of Medicine, New York University School of Medicine, New York, New York 10016, USA.
authors.forename: Aleena
authors.initials: A
authors.lastname: Zahra
authors.affiliation: Division of Infectious Diseases, Department of Medicine, New York University School of Medicine, New York, New York 10016, USA.
authors.forename: Thais
authors.initials: T
authors.lastname: Klevorn
authors.affiliation: Division of Infectious Diseases, Department of Medicine, New York University School of Medicine, New York, New York 10016, USA.
authors.forename: Patricia S
authors.initials: PS
authors.lastname: Grace
authors.affiliation: Division of Infectious Diseases, Department of Medicine, New York University School of Medicine, New York, New York 10016, USA.
authors.forename: Alka
authors.initials: A
authors.lastname: Mehra
authors.affiliation: Division of Infectious Diseases, Department of Medicine, New York University School of Medicine, New York, New York 10016, USA.
authors.forename: Heidi S
authors.initials: HS
authors.lastname: Park
authors.affiliation: Division of Infectious Diseases, Department of Medicine, New York University School of Medicine, New York, New York 10016, USA.
authors.forename: Joel D
authors.initials: JD
authors.lastname: Ernst
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.|Howards Hughes Medical Institute, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Jacobs
authors.affiliation: Division of Infectious Diseases, Department of Medicine, New York University School of Medicine, New York, New York 10016, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Philips
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D004195:Disease Models, Animal; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism*; D015870:Gene Expression; D055786:Gene Knockout Techniques; D054884:Host-Pathogen Interactions; D057131:Immune Evasion; D008213:Lymphocyte Activation; D008264:Macrophages / Q000276:immunology; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D014376:Tuberculosis / Q000382:microbiology / Q000473:pathology
chemical_list: D001426:Bacterial Proteins; D056827:Endosomal Sorting Complexes Required for Transport