Crucial roles of XCR1-expressing dendritic cells and the XCR1-XCL1 chemokine axis in intestinal immune homeostasis.

Intestinal immune homeostasis is regulated by a variety of innate and adaptive immune cells1, including dendritic cells (DCs)2,3. The DC population is heterogeneous, consisting of several subsets with specific functions, distinguished by characteristic patterns of surface marker expression4,5. In mice, CD103+CD11b− and CD103−CD11b+ DC subsets are present in the spleen and lymph nodes (LNs), while in the lamina propria (LP) of the intestine, an additional CD103+CD11b+ subset exists4,5. The roles of the various intestinal DC subsets are variously well-studied: CD103+CD11b+ DCs are the most abundant and are involved in generating Th17 and regulatory T (Treg) cells6,7,8,9, and anti-fungal immunity10; CD103−CD11b+ DCs are related to macrophages2 and play an immunoregulatory role via the secretion of IL-10 and TGF-β111,12; while in contrast, little is known of the role of CD103+CD11b− DCs in this site. CD103+CD11b− DCs also express the T cell co-receptor CD8α and the chemokine receptor XCR1 (lymphotactin receptor/G-protein-coupled receptor 5), and represent approximately 5% of murine intestinal DCs13,14,15,16. This subset (hereafter “XCR1+ DCs”) also exists in other tissues including spleen, LNs and skin, where it specializes in the uptake of dead cells and cross-presentation of antigen to CD8+ T cells17, which is important for protection against viruses, bacteria and parasites, and for anti-tumour immunity14,16,18,19,20,21. XCR1+ DCs are also present in other mammalian species22,23; in humans, XCR1 is expressed on a DC subset that is present in various tissues, including skin and blood, and possesses high cross-presenting activity24. How the XCR1+ DC subset functions in either the murine or human intestine is currently unknown. The ligand for XCR1 is XCL1 in mice and XCL1 and XCL2 in humans25. In both species, XCL1 is produced mainly by natural killer (NK) and activated CD8+ T cells15,16,17,18,22,23. Mice lacking XCR1 or XCL1 show diminished CD8+ T cell responses against the antigens cross-presented by CD103+CD11b− DCs15; XCL1 is also involved in regulating medullary accumulation of thymic XCR1+ DCs, and thymic generation of naturally-occurring regulatory T (Treg) cells26. Thus, the XCR1-XCL1 axis has the potential to modulate both the localization and function of T cells and DCs, though the extent to which this is relevant outside of the thymic environment is not yet clear. In order to clarify the functions of XCR1+ DCs, we generated and analysed mutant mice in which these cells are constitutively ablated. These mice possessed significantly fewer intestinal T cells than their wildtype counterparts, and the remaining T cells exhibited an atypical phenotype. Consistent with the regulatory roles of intestinal T cells, XCR1+ DC-deficient mice showed exaggerated manifestations during chemically-induced colitis. Alongside, in mice lacking either XCR1 or XCL1, a similar decrease in T cell populations was seen, accompanied by an accumulation of CD103+CD11b− DCs in the intestine. Thus, we have identified novel regulatory roles of XCR1+ DC and the XCR1-XCL1 axis in maintaining intestinal immune homeostasis, and have proposed a hypothetical model on which to base future studies to define the underlying mechanisms.