CD8(+) T cells specific to a single Yersinia pseudotuberculosis epitope restrict bacterial replication in the liver but fail to provide sterilizing immunity.
CD8(+) T cells use contact-dependent cytolysis of target cells to protect the host against intracellular pathogens. We have previously shown that CD8(+) T cells and perforin are required to protect against the extracellular pathogen Yersinia pseudotuberculosis. Here we establish an experimental system where CD8(+) T cells specific to a single model antigen are the only memory response present at time of challenge. Using mice immunized with a vaccine strain of Listeria monocytogenes that expresses secreted ovalbumin (Lm-OVA), we show that OVA-specific CD8(+) T cells are generated and provide limited protection against challenge with virulent OVA(+)Y. pseudotuberculosis. Perforin expression by OVA-specific CD8(+) T cells was required, as Lm-OVA-immunized perforin-deficient mice showed higher bacterial burden as compared to Lm-OVA-immunized perforin-sufficient mice. Surprisingly, antigen-specific T cell protection waned over time, as Lm-OVA-immune mice eventually succumbed to Yersinia infection. Kinetic analysis of infection in mice with and without OVA-specific CD8(+) T cells revealed that bacterial numbers increased sharply in OVA-naïve mice until death, while OVA-immune mice held bacterial burden to a lower level throughout the duration of illness until death. Clonal analysis of bacterial populations in OVA-naïve and OVA-immune mice at distinct time points revealed equivalent and severe bottle-neck effects for bacteria in both sets of mice immediately after intravenous challenge, demonstrating a dominant role for other aspects of the immune system regardless of CD8(+) T cell status. These studies indicate that CD8(+) T cells against a single antigen can restrict Y. pseudotuberculosis colonization in a perforin-dependent manner, but ultimately are insufficient in their ability to provide sterilizing immunity and protect against death.
Department of Microbiology & Immunology, The University of Texas Health Sciences Center San Antonio, San Antonio, TX, USA.
Haiqian
H
Shen
Department of Microbiology, The University of Alabama at Birmingham, Birmingham, AL, USA.
Norberto
N
Gonzalez-Juarbe
Department of Microbiology & Immunology, The University of Texas Health Sciences Center San Antonio, San Antonio, TX, USA.
Krystle
K
Blanchette
Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA, USA.
Gregory
G
Crimmins
Department of Microbiology & Immunology, The University of Texas Health Sciences Center San Antonio, San Antonio, TX, USA.
Molly A
MA
Bergman
Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA, USA; Howard Hughes Medical Institute, Tufts University School of Medicine, Boston, MA, USA.
Ralph R
RR
Isberg
Department of Microbiology, The University of Alabama at Birmingham, Birmingham, AL, USA.
Carlos J
CJ
Orihuela
Department of Microbiology & Immunology, The University of Texas Health Sciences Center San Antonio, San Antonio, TX, USA. Electronic address: dube@uthscsa.edu.
Peter H
PH
Dube
D000818:Animals; D000941:Antigens / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D058491:Bacterial Load; D001428:Bacterial Vaccines / Q000008:administration & dosage*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000382:microbiology; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D005260:Female; D015870:Gene Expression; D007156:Immunologic Memory; D008089:Listeria monocytogenes / Q000737:chemistry / Q000276:immunology; D008099:Liver / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010047:Ovalbumin / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D052899:Pore Forming Cytotoxic Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D016019:Survival Analysis; D015011:Yersinia pseudotuberculosis / Q000187:drug effects / Q000254:growth & development / Q000472:pathogenicity*; D015012:Yersinia pseudotuberculosis Infections / Q000276:immunology* / Q000382:microbiology / Q000401:mortality / Q000517:prevention & control
D000941:Antigens; D001428:Bacterial Vaccines; D018984:Epitopes, T-Lymphocyte; D052899:Pore Forming Cytotoxic Proteins; C483886:perforin, mouse; D010047:Ovalbumin
Bottle-neck; CD8(+) T cells; Ovalbumin; Perforin; Yersinia pseudotuberculosis; YopE