Apoptotic vesicles crossprime CD8 T cells and protect against tuberculosis.
CD8 T lymphocytes are important effectors in protective immunity against Mycobacterium tuberculosis. We recently characterized the detour pathway of CD8 T cell activation in tuberculosis mediated by apoptotic vesicles from infected cells that transport mycobacterial antigens to dendritic cells (DCs). Here we demonstrate that apoptotic vesicles from mycobacteria-infected macrophages stimulate CD8 T cells in vivo. Homing of DCs to draining lymph nodes was critically required for effective crosspriming. Subsequent fate of vesicle-associated antigens in recipient DCs was characterized by endosomal mechanisms predominating over proteasomal processing. In addition, vesicle processing depended on the presence of saposins to disintegrate apoptotic membranes. Apoptotic vesicles displayed potent adjuvant activity by stimulating through Toll-like receptors (TLR). Ultimately, vaccination with vesicles from infected cells induced protection against M. tuberculosis infection. Taken together, we propose the detour pathway to represent a genuine immunological mechanism mediating crosspriming of CD8 T cells in vivo and protection against tuberculosis.
Winau
Florian
F
Department of Immunology, Max-Planck-Institute for Infection Biology, Schumannstrasse 21-22, 10117 Berlin, Germany. winau@mpiib-berlin.mpg.de
Weber
Stephan
S
Sad
Subash
S
de Diego
Juana
J
Hoops
Silvia Locatelli
SL
Breiden
Bernadette
B
Sandhoff
Konrad
K
Brinkmann
Volker
V
Kaufmann
Stefan H E
SH
Schaible
Ulrich E
UE
D000276:Adjuvants, Immunologic / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis; D001500:BCG Vaccine / Q000276:immunology / Q000627:therapeutic use*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045142:Cross-Priming / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D011992:Endosomes / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D008264:Macrophages / Q000382:microbiology / Q000648:ultrastructure; D051379:Mice; D009163:Mycobacterium bovis / Q000276:immunology; D049231:Saposins / Q000378:metabolism; D051193:Toll-Like Receptors / Q000276:immunology; D014376:Tuberculosis / Q000276:immunology / Q000517:prevention & control*; D014611:Vaccination / Q000379:methods
D000276:Adjuvants, Immunologic; D001500:BCG Vaccine; D049231:Saposins; D051193:Toll-Like Receptors