Human BDCA3+ dendritic cells (DCs) were suggested to be homologous to mouse CD8α+ DCs. We demonstrate that human BDCA3+ DCs are more efficient than their BDCA1+ counterparts or plasmacytoid DCs (pDCs) in cross-presenting antigen and activating CD8+ T cells, which is similar to mouse CD8α+ DCs as compared with CD11b+ DCs or pDCs, although with more moderate differences between human DC subsets. Yet, no specific marker was known to be shared between homologous DC subsets across species. We found that XC chemokine receptor 1 (XCR1) is specifically expressed and active in mouse CD8α+, human BDCA3+, and sheep CD26+ DCs and is conserved across species. The mRNA encoding the XCR1 ligand chemokine (C motif) ligand 1 (XCL1) is selectively expressed in natural killer (NK) and CD8+ T lymphocytes at steady-state and is enhanced upon activation. Moreover, the Xcl1 mRNA is selectively expressed at high levels in central memory compared with naive CD8+ T lymphocytes. Finally, XCR1−/− mice have decreased early CD8+ T cell responses to Listeria monocytogenes infection, which is associated with higher bacterial loads early in infection. Therefore, XCR1 constitutes the first conserved specific marker for cell subsets homologous to mouse CD8α+ DCs in higher vertebrates and promotes their ability to activate early CD8+ T cell defenses against an intracellular pathogenic bacteria.

SignificanceCancer immunotherapy is a promising therapeutic intervention. However, complete and durable responses are seen in only a fraction of cancer patients. A key factor that limits therapeutic success is the lack of T cells in tumor cell regions, a profile termed “immune-excluded.” Here, we provide evidence that tumor-associated macrophages (TAMs) are an important determinant of the establishment of a T cell-excluded tumor phenotype. In human and murine tumors, we found that CD8 T cells poorly migrate and invade tumor nests due to long-lasting interactions with TAMs. The depletion of TAMs restores T cell migration and infiltration into tumor islets and improves the efficacy of anti–PD-1 immunotherapy. This study highlights the rationale of combining approaches targeting TAM and immune checkpoint proteins.