title: Apoptosis facilitates antigen presentation to T lymphocytes through MHC-I and CD1 in tuberculosis.
abstract: Protective immunity against Mycobacterium tuberculosis involves major histocompatibility complex class I (MHC-I)- and CD1-restricted CD8 T cells, but the mechanisms underlying antigen delivery to antigen-presenting molecules remain enigmatic. Macrophages, the primary host cells for mycobacteria, are CD1-negative. Here we show that M. tuberculosis phagosomes are secluded from the cytosolic MHC-I processing pathway and that mycobacteria-infected cells lose their antigen-presenting capacity. We also show that mycobacteria induce apoptosis in macrophages, causing the release of apoptotic vesicles that carry mycobacterial antigens to uninfected antigen-presenting cells (APCs). Inhibition of apoptosis reduced transfer of antigens to bystander cells and activation of CD8 T cells. Uninfected dendritic cells, which engulfed extracellular vesicles, were indispensable for subsequent cross-presentation of antigens, through MHC-I and CD1b, to T cells from mycobacteria-sensitized donors. This new 'detour' pathway for presentation of antigens from a phagosome-contained pathogen shows the functional significance of infection-induced apoptosis in the activation of CD8 T cells specific for both protein and glycolipid antigens in tuberculosis.
authors.affiliation: Max-Planck Institute for Infection Biology, Department of Immunology, Schumannstrasse 21-22, D-10117 Berlin, Germany. schaible@mpiib-berlin.mpg.de
authors.forename: Ulrich E
authors.initials: UE
authors.lastname: Schaible
authors.forename: Florian
authors.initials: F
authors.lastname: Winau
authors.forename: Peter A
authors.initials: PA
authors.lastname: Sieling
authors.forename: Karsten
authors.initials: K
authors.lastname: Fischer
authors.forename: Helen L
authors.initials: HL
authors.lastname: Collins
authors.forename: Kristine
authors.initials: K
authors.lastname: Hagens
authors.forename: Robert L
authors.initials: RL
authors.lastname: Modlin
authors.forename: Volker
authors.initials: V
authors.lastname: Brinkmann
authors.forename: Stefan H E
authors.initials: SH
authors.lastname: Kaufmann
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism / Q000648:ultrastructure; D000942:Antigens, Bacterial / Q000276:immunology / Q000378:metabolism; D018949:Antigens, CD1 / Q000276:immunology*; D017209:Apoptosis / Q000502:physiology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D005805:Genes, MHC Class I; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D008089:Listeria monocytogenes / Q000166:cytology / Q000378:metabolism; D008213:Lymphocyte Activation; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D009169:Mycobacterium tuberculosis / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D010588:Phagosomes / Q000378:metabolism; D014376:Tuberculosis / Q000276:immunology*
chemical_list: D000942:Antigens, Bacterial; D018949:Antigens, CD1; D015395:Histocompatibility Antigens Class I