Suppression of cell-mediated immunity following recognition of phagosome-confined bacteria.
Listeria monocytogenes is a facultative intracellular pathogen capable of inducing a robust cell-mediated immune response to sub-lethal infection. The capacity of L. monocytogenes to escape from the phagosome and enter the host cell cytosol is paramount for the induction of long-lived CD8 T cell-mediated protective immunity. Here, we show that the impaired T cell response to L. monocytogenes confined within a phagosome is not merely a consequence of inefficient antigen presentation, but is the result of direct suppression of the adaptive response. This suppression limited not only the adaptive response to vacuole-confined L. monocytogenes, but negated the response to bacteria within the cytosol. Co-infection with phagosome-confined and cytosolic L. monocytogenes prevented the generation of acquired immunity and limited expansion of antigen-specific T cells relative to the cytosolic L. monocytogenes strain alone. Bacteria confined to a phagosome suppressed the production of pro-inflammatory cytokines and led to the rapid MyD88-dependent production of IL-10. Blockade of the IL-10 receptor or the absence of MyD88 during primary infection restored protective immunity. Our studies demonstrate that the presence of microbes within a phagosome can directly impact the innate and adaptive immune response by antagonizing the signaling pathways necessary for inflammation and the generation of protective CD8 T cells.
Bahjat
Keith S
KS
Earle A. Chiles Research Institute, Robert W. Franz Cancer Research Center, Providence Cancer Center, Portland, Oregon, United States of America. keith.bahjat@providence.org
Meyer-Morse
Nicole
N
Lemmens
Edward E
EE
Shugart
Jessica A
JA
Dubensky
Thomas W
TW
Brockstedt
Dirk G
DG
Portnoy
Daniel A
DA
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D003600:Cytosol; D005434:Flow Cytometry; D054884:Host-Pathogen Interactions / Q000276:immunology; D007111:Immunity, Cellular; D008089:Listeria monocytogenes / Q000276:immunology* / Q000472:pathogenicity; D008088:Listeriosis / Q000276:immunology* / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism; D010588:Phagosomes / Q000276:immunology* / Q000382:microbiology; D053701:Receptors, Interleukin-10 / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology / Q000276:immunology
D016207:Cytokines; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D053701:Receptors, Interleukin-10