The mouse lymphoid organ-resident CD8α+ dendritic cell (DC) subset is specialized in Ag presentation to CD8+ T cells. Recent evidence shows that mouse nonlymphoid tissue CD103+ DCs and human blood DC Ag 3+ DCs share similarities with CD8α+ DCs. We address here whether the organization of DC subsets is conserved across mammals in terms of gene expression signatures, phenotypic characteristics, and functional specialization, independently of the tissue of origin. We study the DC subsets that migrate from the skin in the ovine species that, like all domestic animals, belongs to the Laurasiatheria, a distinct phylogenetic clade from the supraprimates (human/mouse). We demonstrate that the minor sheep CD26+ skin lymph DC subset shares significant transcriptomic similarities with mouse CD8α+ and human blood DC Ag 3+ DCs. This allowed the identification of a common set of phenotypic characteristics for CD8α-like DCs in the three mammalian species (ie, SIRP lo, CADM1 hi, CLEC9A hi, CD205 hi, XCR1 hi). Compared to CD26− DCs, the sheep CD26+ DCs show 1) potent stimulation of allogeneic naive CD8+ T cells with high selective induction of the Ifnγ and Il22 genes; 2) dominant efficacy in activating specific CD8+ T cells against exogenous soluble Ag; and 3) selective expression of functional pathways associated with high capacity for Ag cross-presentation. Our results unravel a unifying definition of the CD8α+-like DCs across mammalian species and identify molecular candidates that could be used for the design of vaccines applying to mammals in general.

Migratory and lymphoid organ-resident dendritic cells (DCs) include several DC subtypes that are endowed with specific functions involved in the establishment of tolerance or immunity. The plasmacytoid DC (pDC) subset is a professional producer of the antiviral cytokines IFN-α and IFN-β (1). In the mouse, the CD11c hi lymphoid tissue conventional DCs (LT-DCs) can be divided into CD8α+ and CD11b+ subsets (reviewed in Refs. 2, 3). CD11b+ LT-DCs are generally more efficient than the CD8α+ DCs at MHC class II Ag presentation (4–6). Conversely, in most instances, the CD8α+ DCs are more capable than the CD11b+ DCs for cross-priming CD8+ T cells after the processing of endocytosed exogenous or self Ags (6, 7). This functional specialization of the CD8α+ DCs for CD8+ T cell activation relies on a number of intrinsic molecular properties. First, CD8α+ LT-DCs express several components of the molecular machinery for MHC class I Ag processing and presentation to higher levels than CD11b+ LT-DCs (6). They produce high levels of biologically active IL-12, which contributes to promote the activation and the functional polarization of CD8+ T cells toward polyfunctional effector or memory subsets (6, 8). They show a higher efficiency for uptake of apoptotic bodies (9) due to their selective expression of certain scavenger receptors. They express high levels of the CLEC9A protein, which routes engulfed dead cell fragments toward a specialized phago-/endosomal compartment dedicated to cross-presentation (10, 11). They also display a tight control of the phago-/endosomal acidification that is related to moderate activity in Ag degradation (12). Finally, they have the ability to export engulfed materials to the cytosol (13). Recently, a similar functional specialization for CD8+ T cell activation has been ascribed to non-LT migratory CD103+ DCs in the lung (14), intestine (15), and skin (16–18). Interestingly, most of the non-LT CD103+ DCs, except gut CD11b+ CD103+ DCs, were found to be related to the LT CD8α+ DCs in that they derive from the same precursor in a …