Abstract
Our previous studies in volunteers immunized with Salmonella enterica serovar Typhi (S. Typhi) have suggested an important role for CD8+ T cells in host defense. In this study we describe a novel subset of nonclassical human HLA-E-restricted S. Typhi-specific CD8+ T cells derived from PBMC of Ty21a typhoid vaccinees. CD3+CD8+CD4-CD56- T cells effectively killed S. Typhi-infected targets regardless of whether they share classical HLA class I molecules with them, by a FAS-independent, granule-dependent mechanism, as evidenced by induction of granzyme B release and the blocking effects of concanamycin and strontium ions. The expression of HLA-E Ags, but not CD1-a, -b, or -c, on the membrane of S. Typhi-infected targets rendered them susceptible to lysis. Moreover, anti-HLA-E Abs partially blocked these responses. We also demonstrated that presentation of S. Typhi Ags via HLA-E could stimulate IFN-gamma production. Increases in the net frequency of IFN-gamma spot-forming cells were observed in the presence of targets coated with peptides that contain S. Typhi GroEL HLA-E binding motifs. These results demonstrate that HLA-E binds nonamer peptides derived from bacterial proteins and trigger CD8+-mediated lysis and IFN-gamma production when exposed to infected targets, raising the possibility that this novel effector mechanism might contribute to host defense against intracellular bacterial infections.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adult
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Antibodies, Blocking / metabolism
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Antibodies, Monoclonal / metabolism
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Antigen Presentation / immunology
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Antigen-Presenting Cells / enzymology
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Antigen-Presenting Cells / immunology
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Antigens, Bacterial / immunology
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Antigens, Bacterial / metabolism
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Binding Sites, Antibody
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CD3 Complex / biosynthesis
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CD56 Antigen / biosynthesis
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CD8-Positive T-Lymphocytes / immunology*
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CD8-Positive T-Lymphocytes / microbiology
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Cell Line
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Cell Line, Transformed
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Cytoplasmic Granules / enzymology
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Cytoplasmic Granules / immunology
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Cytoplasmic Granules / microbiology
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Cytotoxicity Tests, Immunologic* / methods
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HLA Antigens / immunology*
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HLA Antigens / metabolism
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HLA-E Antigens
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Histocompatibility Antigens Class I / immunology*
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Histocompatibility Antigens Class I / metabolism
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Humans
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Lymphocyte Count
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Middle Aged
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Peptide Fragments / immunology
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Peptide Fragments / metabolism
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Proteasome Endopeptidase Complex / metabolism
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Protein Binding / immunology
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Protein Processing, Post-Translational / immunology
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Salmonella typhi / immunology*
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T-Lymphocytes, Cytotoxic / immunology*
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T-Lymphocytes, Cytotoxic / microbiology
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Typhoid-Paratyphoid Vaccines / administration & dosage
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Typhoid-Paratyphoid Vaccines / immunology*
Substances
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Antibodies, Blocking
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Antibodies, Monoclonal
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Antigens, Bacterial
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CD3 Complex
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CD56 Antigen
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HLA Antigens
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Histocompatibility Antigens Class I
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Peptide Fragments
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Typhoid-Paratyphoid Vaccines
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Proteasome Endopeptidase Complex