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 motifcontaining DC immunoreceptor (DCIR) to mediate potent cross-presentation. A single exposure to a low dose of anti-DCIR-antigen conjugate initiated antigenspecific 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.