title: Rv2468c, a novel Mycobacterium tuberculosis protein that costimulates human CD4+ T cells through VLA-5.
abstract: Mtb regulates many aspects of the host immune response, including CD4+ T lymphocyte responses that are essential for protective immunity to Mtb, and Mtb effects on the immune system are paradoxical, having the capacity to inhibit (immune evasion) and to activate (adjuvant effect) immune cells. Mtb regulates CD4+ T cells indirectly (e.g., by manipulation of APC function) and directly, via integrins and TLRs expressed on T cells. We now report that previously uncharacterized Mtb protein Rv2468c/MT2543 can directly regulate human CD4+ T cell activation by delivering costimulatory signals. When combined with TCR stimulation (e.g., anti-CD3), Rv2468c functioned as a direct costimulator for CD4+ T cells, inducing IFN-γ secretion and T cell proliferation. Studies with blocking antibodies and soluble RGD motifs demonstrated that Rv2468c engaged integrin VLA-5 (α5β1) on CD4+ T cells through its FN-like RGD motif. Costimulation by Rv2468c induced phosphorylation of FAKs and Pyk2. These results reveal that by expressing molecules that mimic host protein motifs, Mtb can directly engage receptors on CD4+ T cells and regulate their function. Rv2468c-induced costimulation of CD4+ T cells could have implications for TB immune pathogenesis and Mtb adjuvant effect.
authors.affiliation: Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Li
authors.forename: Xuedong
authors.initials: X
authors.lastname: Ding
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Thomas
authors.forename: Clifford V
authors.initials: CV
authors.lastname: Harding
authors.forename: Nicole D
authors.initials: ND
authors.lastname: Pecora
authors.forename: Assem G
authors.initials: AG
authors.lastname: Ziady
authors.forename: Samuel
authors.initials: S
authors.lastname: Shank
authors.forename: W Henry
authors.initials: WH
authors.lastname: Boom
authors.forename: Christina L
authors.initials: CL
authors.lastname: Lancioni
authors.forename: Roxana E
authors.initials: RE
authors.lastname: Rojas
mesh_terms: D001426:Bacterial Proteins / Q000737:chemistry / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D051418:Focal Adhesion Kinase 2 / Q000378:metabolism; D006801:Humans; D007156:Immunologic Memory; D039482:Integrin alpha5 / Q000737:chemistry; D039081:Integrin alpha5beta1 / Q000737:chemistry / Q000502:physiology*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology*; D009169:Mycobacterium tuberculosis / Q000502:physiology*; D009842:Oligopeptides; D010766:Phosphorylation; D011485:Protein Binding; D025941:Protein Interaction Mapping; D011499:Protein Processing, Post-Translational; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D015398:Signal Transduction / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics; D015854:Up-Regulation
chemical_list: D001426:Bacterial Proteins; D039482:Integrin alpha5; D039081:Integrin alpha5beta1; D009842:Oligopeptides; D011948:Receptors, Antigen, T-Cell; C570836:Rv2468c protein, Mycobacterium tuberculosis; D014409:Tumor Necrosis Factor-alpha; C047981:arginyl-glycyl-aspartic acid; D007371:Interferon-gamma; D051417:Focal Adhesion Kinase 1; D051418:Focal Adhesion Kinase 2; C496050:PTK2 protein, human