Apoptosis Facilitates Antigen Presentation to T Lymphocytes Through MHC-I and CD1 in Tuberculosis

Nat Med. 2003 Aug;9(8):1039-46. doi: 10.1038/nm906. Epub 2003 Jul 20.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigen Presentation*
  • Antigen-Presenting Cells / immunology
  • Antigen-Presenting Cells / metabolism
  • Antigen-Presenting Cells / ultrastructure
  • Antigens, Bacterial / immunology
  • Antigens, Bacterial / metabolism
  • Antigens, CD1 / immunology*
  • Apoptosis / physiology*
  • CD8-Positive T-Lymphocytes / immunology*
  • Genes, MHC Class I
  • Histocompatibility Antigens Class I / immunology*
  • Humans
  • Listeria monocytogenes / cytology
  • Listeria monocytogenes / metabolism
  • Lymphocyte Activation
  • Macrophages / immunology
  • Macrophages / metabolism
  • Mice
  • Mycobacterium tuberculosis / cytology
  • Mycobacterium tuberculosis / immunology
  • Mycobacterium tuberculosis / metabolism
  • Phagosomes / metabolism
  • Tuberculosis / immunology*

Substances

  • Antigens, Bacterial
  • Antigens, CD1
  • Histocompatibility Antigens Class I