CD8(+) T cells restrict Yersinia pseudotuberculosis infection: bypass of anti-phagocytosis by targeting antigen-presenting cells.
All Yersinia species target and bind to phagocytic cells, but uptake and destruction of bacteria are prevented by injection of anti-phagocytic Yop proteins into the host cell. Here we provide evidence that CD8(+) T cells, which canonically eliminate intracellular pathogens, are important for restricting Yersinia, even though bacteria are primarily found in an extracellular locale during the course of disease. In a model of infection with attenuated Y. pseudotuberculosis, mice deficient for CD8(+) T cells were more susceptible to infection than immunocompetent mice. Although exposure to attenuated Y. pseudotuberculosis generated T(H)1-type antibody responses and conferred protection against challenge with fully virulent bacteria, depletion of CD8(+) T cells during challenge severely compromised protective immunity. Strikingly, mice lacking the T cell effector molecule perforin also succumbed to Y. pseudotuberculosis infection. Given that the function of perforin is to kill antigen-presenting cells, we reasoned that cell death marks bacteria-associated host cells for internalization by neighboring phagocytes, thus allowing ingestion and clearance of the attached bacteria. Supportive of this model, cytolytic T cell killing of Y. pseudotuberculosis-associated host cells results in engulfment by neighboring phagocytes of both bacteria and target cells, bypassing anti-phagocytosis. Our findings are consistent with a novel function for cell-mediated immune responses protecting against extracellular pathogens like Yersinia: perforin and CD8(+) T cells are critical for hosts to overcome the anti-phagocytic action of Yops.
Bergman
Molly A
MA
Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, Massachusetts, United States of America.
Loomis
Wendy P
WP
Mecsas
Joan
J
Starnbach
Michael N
MN
Isberg
Ralph R
RR
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology*; D001428:Bacterial Vaccines / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D004195:Disease Models, Animal; D054884:Host-Pathogen Interactions / Q000276:immunology; D007074:Immunoglobulin G / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008099:Liver / Q000276:immunology / Q000382:microbiology; D008221:Lymphoid Tissue / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D010587:Phagocytosis; D052899:Pore Forming Cytotoxic Proteins / Q000276:immunology; D018709:Statistics, Nonparametric; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D014613:Vaccines, Attenuated / Q000276:immunology; D015011:Yersinia pseudotuberculosis / Q000276:immunology* / Q000472:pathogenicity; D015012:Yersinia pseudotuberculosis Infections / Q000276:immunology*
D001428:Bacterial Vaccines; D007074:Immunoglobulin G; D052899:Pore Forming Cytotoxic Proteins; D014613:Vaccines, Attenuated; C483886:perforin, mouse