Cross-priming CD8+ T cells by targeting antigens to human dendritic cells through DCIR.
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.
Klechevsky
Eynav
E
Baylor Institute for Immunology Research and Inserm U899, Dallas, TX 75204, USA.
Flamar
Anne-Laure
AL
Cao
Yanying
Y
Blanck
Jean-Philippe
JP
Liu
Maochang
M
O'Bar
Amy
A
Agouna-Deciat
Olivier
O
Klucar
Peter
P
Thompson-Snipes
Luann
L
Zurawski
Sandra
S
Reiter
Yoram
Y
Palucka
A Karolina
AK
Zurawski
Gerard
G
Banchereau
Jacques
J
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000941:Antigens / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D045142:Cross-Priming / Q000187:drug effects / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D007801:Langerhans Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D037181:Lectins, C-Type / Q000276:immunology* / Q000378:metabolism; D058965:MART-1 Antigen; D008562:Membrane Glycoproteins / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D009363:Neoplasm Proteins / Q000276:immunology; D011804:Quinolines / Q000494:pharmacology; D011971:Receptors, Immunologic / Q000276:immunology* / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology; D051199:Toll-Like Receptor 7 / Q000819:agonists; D051200:Toll-Like Receptor 8 / Q000819:agonists; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000276:immunology
D000911:Antibodies, Monoclonal; D000941:Antigens; D000951:Antigens, Neoplasm; C551788:CL 075; C423004:CLEC4A protein, human; D037181:Lectins, C-Type; D058965:MART-1 Antigen; C548667:MLANA protein, human; D008562:Membrane Glycoproteins; C548668:Mlana protein, mouse; D009363:Neoplasm Proteins; D011804:Quinolines; D011971:Receptors, Immunologic; D013844:Thiazoles; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D054301:gag Gene Products, Human Immunodeficiency Virus