Abstract
Exogenous heat shock protein (HSP):peptide complexes are processed for cross-presentation of HSP-chaperoned peptides on class I MHC (MHC-I) molecules. Fusion proteins containing HSP and Ag sequences facilitate MHC-I cross-presentation of linked antigenic epitopes. Processing of HSP-associated Ag has been attributed to dendritic cells and macrophages. We now provide the first evidence to show processing of HSP-associated Ag for MHC-I cross-presentation by B lymphocytes. Fusion of OVA sequence (rOVA, containing OVA(230-359) sequence) to Mycobacterium tuberculosis HSP70 greatly enhanced rOVA processing and MHC-I cross-presentation of OVA(257-264):K(b) complexes by B cells. Enhanced processing was dependent on linkage of rOVA sequence to HSP70. M. tuberculosis HSP70-OVA fusion protein enhanced cross-processing by a CD91-dependent process that was independent of TLR4 and MyD88. The enhancement occurred through a post-Golgi, proteasome-independent mechanism. These results indicate that HSPs enhance delivery and cross-processing of HSP-linked Ag by B cells, which could provide a novel contribution to the generation of CD8(+) T cell responses. HSP fusion proteins have potential advantages for use in vaccines to enhance priming of CD8(+) T cell responses.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adjuvants, Immunologic / genetics
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Adjuvants, Immunologic / physiology*
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Animals
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Antigen Presentation / genetics
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Antigen Presentation / immunology*
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Antigens, CD / physiology
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B-Lymphocyte Subsets / immunology*
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B-Lymphocyte Subsets / metabolism*
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Bacterial Proteins
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Cross-Priming / genetics
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Cross-Priming / immunology*
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Epitopes, B-Lymphocyte / genetics
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Epitopes, B-Lymphocyte / immunology
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Epitopes, B-Lymphocyte / metabolism
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HSP70 Heat-Shock Proteins / genetics
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HSP70 Heat-Shock Proteins / physiology*
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Histocompatibility Antigens Class I / immunology
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Histocompatibility Antigens Class I / metabolism
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Low Density Lipoprotein Receptor-Related Protein-1
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Mycobacterium tuberculosis / genetics
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Mycobacterium tuberculosis / immunology*
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Ovalbumin / genetics
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Ovalbumin / immunology
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Ovalbumin / metabolism
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Peptide Fragments / genetics
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Peptide Fragments / immunology
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Peptide Fragments / metabolism
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Recombinant Fusion Proteins / immunology
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Recombinant Fusion Proteins / metabolism
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Recombinant Fusion Proteins / physiology*
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Vacuoles / genetics
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Vacuoles / immunology
Substances
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Adjuvants, Immunologic
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Antigens, CD
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Bacterial Proteins
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Epitopes, B-Lymphocyte
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HSP70 Heat-Shock Proteins
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HSP70 protein, Mycobacterium tuberculosis
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Histocompatibility Antigens Class I
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LRP1 protein, human
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Low Density Lipoprotein Receptor-Related Protein-1
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Peptide Fragments
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Recombinant Fusion Proteins
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Ovalbumin