Adaptive immunity and enhanced CD8+ T cell response to Listeria monocytogenes in the absence of perforin and IFN-gamma.
Single Ag-specific CD8+ T cells from IFN-gamma-deficient (GKO) or perforin-deficient (PKO) mice provide substantial immunity against murine infection with Listeria monocytogenes. To address the potential for redundancy between perforin and IFN-gamma as CD8+ T cell effector mechanisms, we generated perforin/IFN-gamma (PKO/GKO) double-deficient mice. PKO/GKO-derived CD8+ T cells specific for the immunodominant listeriolysin O (LLO91-99) epitope provide immunity to LM infection similar to that provided by Ag-matched wild-type (WT) CD8+ T cells in the liver but reduced in the spleen. Strikingly, polyclonal CD8+ T cells from immunized PKO/GKO mice were approximately 100-fold more potent in reducing bacterial numbers than the same number of polyclonal CD8+ T cells from immunized WT mice. This result is probably quantitative, because the frequency of the CD8+ T cell response against the immunodominant LLO91-99 epitope is >4.5-fold higher in PKO/GKO mice than WT mice at 7 days after identical immunizations. Moreover, PKO/GKO mice can be immunized by a single infection with attenuated Listeria to resist >80,000-fold higher challenges with virulent organisms than naive PKO/GKO mice. These data demonstrate that neither perforin nor IFN-gamma is required for the development or expression of adaptive immunity to LM. In addition, the results suggest the potential for perforin and IFN-gamma to regulate the magnitude of the CD8+ T cell response to infection.
Badovinac
V P
VP
Department of Microbiology and Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City 52242, USA.
Harty
J T
JT
D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology; D001427:Bacterial Toxins; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D002460:Cell Line; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D020022:Genetic Predisposition to Disease; D006360:Heat-Shock Proteins / Q000276:immunology; D006460:Hemolysin Proteins; D007113:Immunity, Innate / Q000235:genetics; D007371:Interferon-gamma / Q000172:deficiency* / Q000235:genetics*; D008089:Listeria monocytogenes / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity; D008088:Listeriosis / Q000235:genetics / Q000276:immunology* / Q000382:microbiology; D008562:Membrane Glycoproteins / Q000172:deficiency* / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D016176:T-Lymphocyte Subsets / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014774:Virulence / Q000276:immunology; D019014:fas Receptor / Q000502:physiology
D001426:Bacterial Proteins; D001427:Bacterial Toxins; D018984:Epitopes, T-Lymphocyte; D006360:Heat-Shock Proteins; D006460:Hemolysin Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D052899:Pore Forming Cytotoxic Proteins; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D054353:Perforin; C072980:actA protein, Listeria monocytogenes; D007371:Interferon-gamma; C038705:hlyA protein, Listeria monocytogenes