Abstract
We evaluated human CD8(+) T-cell responses generated by targeting antigens to dendritic cells (DCs) through various lectin receptors. We found the immunoreceptor tyrosine-based inhibitory motif-containing DC immunoreceptor (DCIR) to mediate potent cross-presentation. A single exposure to a low dose of anti-DCIR-antigen conjugate initiated antigen-specific CD8(+) T-cell immunity by all human DC subsets including ex vivo-generated DCs, skin-isolated Langerhans cells, and blood myeloid DCs and plasmacytoid DCs. The delivery of influenza matrix protein (FluMP) through DCIR resulted in expansion of FluMP-specific memory CD8(+) T cells. Enhanced specific CD8(+) T-cell responses were observed when an antigen was delivered to the DCs via DCIR, compared with those induced by a free antigen, or antigen conjugated to a control monoclonal antibody or delivered via DC-SIGN, another lectin receptor. DCIR targeting also induced primary CD8(+) T-cell responses against self (MART-1) and viral (HIV gag) antigens. Addition of Toll-like receptor (TLR) 7/8 agonist enhanced DCIR-mediated cross-presentation as well as cross-priming, particularly when combined with a CD40 signal. TLR7/8 activation was associated with increased expansion of the primed CD8(+) T cells, high production of interferon-γ and tumor necrosis factor-α, and reduced levels of type 2-associated cytokines. Thus, antigen targeting via the human DCIR receptor allows activation of specific CD8(+) T-cell immunity.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Monoclonal / immunology
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Antigens / immunology*
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Antigens, Neoplasm / immunology
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B-Lymphocytes / cytology
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B-Lymphocytes / immunology
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B-Lymphocytes / metabolism
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CD8-Positive T-Lymphocytes / cytology
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CD8-Positive T-Lymphocytes / immunology*
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CD8-Positive T-Lymphocytes / metabolism
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Cells, Cultured
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Cross-Priming / drug effects
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Cross-Priming / immunology
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Dendritic Cells / cytology
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Dendritic Cells / immunology*
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Dendritic Cells / metabolism
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Flow Cytometry
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Humans
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Langerhans Cells / cytology
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Langerhans Cells / immunology
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Langerhans Cells / metabolism
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Lectins, C-Type / immunology*
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Lectins, C-Type / metabolism
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MART-1 Antigen
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Membrane Glycoproteins / immunology*
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Membrane Glycoproteins / metabolism
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Mice
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Mice, Inbred BALB C
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Monocytes / cytology
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Monocytes / immunology
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Monocytes / metabolism
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Neoplasm Proteins / immunology
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Quinolines / pharmacology
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Receptors, Immunologic / immunology*
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Receptors, Immunologic / metabolism
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Thiazoles / pharmacology
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Toll-Like Receptor 7 / agonists
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Toll-Like Receptor 8 / agonists
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gag Gene Products, Human Immunodeficiency Virus / immunology
Substances
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Antibodies, Monoclonal
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Antigens
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Antigens, Neoplasm
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CL 075
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CLEC4A protein, human
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Lectins, C-Type
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MART-1 Antigen
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MLANA protein, human
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Membrane Glycoproteins
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Mlana protein, mouse
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Neoplasm Proteins
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Quinolines
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Receptors, Immunologic
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Thiazoles
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Toll-Like Receptor 7
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Toll-Like Receptor 8
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gag Gene Products, Human Immunodeficiency Virus