Concomitant activation and antigen uptake via human dectin-1 results in potent antigen-specific CD8+ T cell responses.
Dectin-1, a C-type lectin recognizing fungal and mycobacterial pathogens, can deliver intracellular signals that activate dendritic cells (DCs), resulting in initiation of immune responses and expansion of Th17 CD4(+) T cell responses. In this paper, we studied the roles of human Dectin-1 (hDectin-1) expressed on DCs in the induction and activation of Ag-specific CD8(+) T cell responses. We first generated an agonistic anti-hDectin-1 mAb, which recognizes the hDectin-1 Glu(143)-Ile(162) region. It bound to in vitro monocyte-derived DCs and to in vivo CD1c(+)CD1a(+) dermal DCs but not to epidermal Langerhans cells. Anti-hDectin-1-mediated DC activation resulted in upregulation of costimulatory molecules and secretion of multiple cytokines and chemokines in a Syk-dependent manner. DCs activated with the anti-hDectin-1 mAb could significantly enhance both neo and foreign Ag-specific CD8(+) T cell responses by promoting both the expansion of CD8(+) T cells and their functional activities. We further demonstrated that delivering Ags to DCs via hDectin-1 using anti-hDectin-1-Ag conjugates resulted in potent Ag-specific CD8(+) T cell responses. Thus, hDectin-1 expressed on DCs can contribute to the induction and activation of cellular immunity against intracellular pathogens, such as mycobacteria, that are recognized by DCs via Dectin-1. Vaccines based on delivering Ags to DCs with an agonistic anti-hDectin-1 mAb could elicit CD8(+) T cell-mediated immunity.
Ni
Ling
L
Baylor Institute for Immunology Research, Dallas, TX 75204, USA.
Gayet
Ingrid
I
Zurawski
Sandra
S
Duluc
Dorothee
D
Flamar
Anne-Laure
AL
Li
Xiao-Hua
XH
O'Bar
Amy
A
Clayton
Sandra
S
Palucka
Anna Karolina
AK
Zurawski
Gerard
G
Banchereau
Jacques
J
Oh
SangKon
S
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000494:pharmacology; D000918:Antibody Specificity / Q000235:genetics; D001666:Binding Sites, Antibody / Q000235:genetics; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism*; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D037181:Lectins, C-Type; D008565:Membrane Proteins / Q000819:agonists / Q000276:immunology / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000276:immunology / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D000099181:Dectin-1
D000911:Antibodies, Monoclonal; D018984:Epitopes, T-Lymphocyte; D037181:Lectins, C-Type; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D011993:Recombinant Fusion Proteins; D000099181:Dectin-1