title: Mycobacterium tuberculosisMembrane Vesicles Inhibit T Cell Activation.
abstract: Mycobacterium tuberculosisutilizes multiple mechanisms to evade host immune responses, and inhibition of effector CD4+T cell responses byM. tuberculosismay contribute to immune evasion. TCR signaling is inhibited byM. tuberculosiscell envelope lipoglycans, such as lipoarabinomannan and lipomannan, but a mechanism for lipoglycans to traffic fromM. tuberculosiswithin infected macrophages to reach T cells is unknown. In these studies, we found that membrane vesicles produced byM. tuberculosisand released from infected macrophages inhibited the activation of CD4+T cells, as indicated by reduced production of IL-2 and reduced T cell proliferation. Flow cytometry and Western blot demonstrated that lipoglycans fromM. tuberculosis-derived bacterial vesicles (BVs) are transferred to T cells, where they inhibit T cell responses. Stimulation of CD4+T cells in the presence of BVs induced expression of GRAIL, a marker of T cell anergy; upon restimulation, these T cells showed reduced ability to proliferate, confirming a state of T cell anergy. Furthermore, lipoarabinomannan was associated with T cells after their incubation with infected macrophages in vitro and when T cells were isolated from lungs ofM. tuberculosis-infected mice, confirming the occurrence of lipoarabinomannan trafficking to T cells in vivo. These studies demonstrate a novel mechanism for the direct regulation of CD4+T cells byM. tuberculosislipoglycans conveyed by BVs that are produced byM. tuberculosisand released from infected macrophages. These lipoglycans are transferred to T cells to inhibit T cell responses, providing a mechanism that may promote immune evasion.
authors.affiliation: Department of Pathology, Case Western Reserve University and University Hospitals Cleveland Medical Center, Cleveland, OH 44106.
authors.forename: Jaffre J
authors.identifier: 0000-0002-9591-0335
authors.initials: JJ
authors.lastname: Athman
authors.affiliation: Department of Pathology, Case Western Reserve University and University Hospitals Cleveland Medical Center, Cleveland, OH 44106.|Department of Molecular Biology and Microbiology, Case Western Reserve University and University Hospitals Cleveland Medical Center, Cleveland, OH 44106.
authors.forename: Obondo J
authors.initials: OJ
authors.lastname: Sande
authors.affiliation: Department of Pathology, Case Western Reserve University and University Hospitals Cleveland Medical Center, Cleveland, OH 44106.
authors.forename: Sarah G
authors.initials: SG
authors.lastname: Groft
authors.affiliation: Department of Molecular Biology and Microbiology, Case Western Reserve University and University Hospitals Cleveland Medical Center, Cleveland, OH 44106.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Reba
authors.affiliation: Department of Pathology, Case Western Reserve University and University Hospitals Cleveland Medical Center, Cleveland, OH 44106.
authors.forename: Nancy
authors.initials: N
authors.lastname: Nagy
authors.affiliation: Department of Pathology, Case Western Reserve University and University Hospitals Cleveland Medical Center, Cleveland, OH 44106.
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Wearsch
authors.affiliation: Department of Pathology, Case Western Reserve University and University Hospitals Cleveland Medical Center, Cleveland, OH 44106.|Medical Scientist Training Program, Case Western Reserve University and University Hospitals Cleveland Medical Center, Cleveland, OH 44106.
authors.forename: Edward T
authors.identifier: 0000-0002-7576-2603
authors.initials: ET
authors.lastname: Richardson
authors.affiliation: Department of Molecular Biology and Microbiology, Case Western Reserve University and University Hospitals Cleveland Medical Center, Cleveland, OH 44106.|Center for AIDS Research, Case Western Reserve University and University Hospitals Cleveland Medical Center, Cleveland, OH 44106; and.
authors.forename: Roxana
authors.initials: R
authors.lastname: Rojas
authors.affiliation: Department of Molecular Biology and Microbiology, Case Western Reserve University and University Hospitals Cleveland Medical Center, Cleveland, OH 44106.|Center for AIDS Research, Case Western Reserve University and University Hospitals Cleveland Medical Center, Cleveland, OH 44106; and.|Division of Infectious Diseases and HIV Medicine, Case Western Reserve University and University Hospitals Cleveland Medical Center, Cleveland, OH 44106.
authors.forename: W Henry
authors.identifier: 0000-0001-5760-9595
authors.initials: WH
authors.lastname: Boom
authors.affiliation: Department of Pathology, Case Western Reserve University and University Hospitals Cleveland Medical Center, Cleveland, OH 44106.
authors.forename: Supriya
authors.identifier: 0000-0001-7441-6306
authors.initials: S
authors.lastname: Shukla
authors.affiliation: Department of Pathology, Case Western Reserve University and University Hospitals Cleveland Medical Center, Cleveland, OH 44106; cvh3@cwru.edu.|Center for AIDS Research, Case Western Reserve University and University Hospitals Cleveland Medical Center, Cleveland, OH 44106; and.|Division of Infectious Diseases and HIV Medicine, Case Western Reserve University and University Hospitals Cleveland Medical Center, Cleveland, OH 44106.
authors.forename: Clifford V
authors.identifier: 0000-0002-6333-162X
authors.initials: CV
authors.lastname: Harding
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D017635:Clonal Anergy; D005260:Female; D006801:Humans; D057131:Immune Evasion; D008070:Lipopolysaccharides / Q000276:immunology; D008168:Lung / Q000276:immunology* / Q000382:microbiology; D008213:Lymphocyte Activation; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D022142:Secretory Vesicles / Q000276:immunology / Q000382:microbiology*; D014376:Tuberculosis / Q000276:immunology*
chemical_list: D008070:Lipopolysaccharides; C050016:lipoarabinomannan