The study investigates the functional characteristics of human CD141+ dendritic cells (DCs), a unique subset of myeloid DCs found in lymph nodes, bone marrow, tonsils, and blood. CD141+ DCs are characterized by high expression of toll-like receptor 3 (TLR3), production of interferon-β (IFN-β) and interleukin-12p70 (IL-12p70), and superior induction of T helper 1 (Th1) cell responses compared to CD1c+ DCs. Poly I:C-activated CD141+ DCs are more effective at cross-presenting soluble protein antigens to CD8+ cytotoxic T lymphocytes (CTLs) than poly I:C-activated CD1c+ DCs. Importantly, CD141+ DCs can cross-present viral antigens from necrotic virus-infected cells, a function not observed in CD1c+ DCs. These findings establish CD141+ DCs as a distinct and functionally important subset of human DCs, similar to the mouse CD8α+ DC subset, and suggest their potential as targets for vaccines against cancers, viruses, and other pathogens. The study also highlights the complexity and specialized roles of human DC subtypes, which have implications for vaccine design and therapeutic strategies.The study investigates the functional characteristics of human CD141+ dendritic cells (DCs), a unique subset of myeloid DCs found in lymph nodes, bone marrow, tonsils, and blood. CD141+ DCs are characterized by high expression of toll-like receptor 3 (TLR3), production of interferon-β (IFN-β) and interleukin-12p70 (IL-12p70), and superior induction of T helper 1 (Th1) cell responses compared to CD1c+ DCs. Poly I:C-activated CD141+ DCs are more effective at cross-presenting soluble protein antigens to CD8+ cytotoxic T lymphocytes (CTLs) than poly I:C-activated CD1c+ DCs. Importantly, CD141+ DCs can cross-present viral antigens from necrotic virus-infected cells, a function not observed in CD1c+ DCs. These findings establish CD141+ DCs as a distinct and functionally important subset of human DCs, similar to the mouse CD8α+ DC subset, and suggest their potential as targets for vaccines against cancers, viruses, and other pathogens. The study also highlights the complexity and specialized roles of human DC subtypes, which have implications for vaccine design and therapeutic strategies.