CCR2+CD103− intestinal dendritic cells develop from DC-committed precursors and induce interleukin-17 production by T cells

Abstract

The identification of intestinal macrophages (mφs) and dendritic cells (DCs) is a matter of intense debate. Although CD103+ mononuclear phagocytes (MPs) appear to be genuine DCs, the nature and origins of CD103− MPs remain controversial. We show here that intestinal CD103−CD11b+ MPs can be separated clearly into DCs and mφs based on phenotype, gene profile, and kinetics. CD64−CD103−CD11b+ MPs are classical DCs, being derived from Flt3 ligand-dependent, DC-committed precursors, not Ly6Chi monocytes. Surprisingly, a significant proportion of these CD103−CD11b+ DCs express CCR2 and there is a selective decrease in CD103−CD11b+ DCs in mice lacking this chemokine receptor. CCR2+CD103− DCs are present in both the murine and human intestine, drive interleukin (IL)-17a production by T cells in vitro, and show constitutive expression of IL-12/IL-23p40. These data highlight the heterogeneity of intestinal DCs and reveal a bona fide population of CCR2+ DCs that is involved in priming mucosal T helper type 17 (Th17) responses.

Diversity and functions of intestinal mononuclear phagocytes

“…7,8 In compliance with the current definition of cDC these cells express FMS-like tyrosine kinase 3 (FLT3/CD135), the receptor for the cDC-specific growth factor FLT3 ligand (FLT3L) and show dependence on this receptor-ligand pathway for their development from cDC precursors in the BM. 8,9 They also express the zinc finger and BTB domain containing 46 (Zbtb46) transcription factor (TF), 8,10 have a lifespan in the tissue of only a few days, and have the capacity to migrate in afferent lymph to the draining lymph nodes, where they can prime naïve T cells. 2,3,5 In contrast, cells of the monocyte-m lineage are CD64 + CD11b + ( Table 2; Figure 1 A, D), are independent of FLT3 signalling, but require the colony stimulating factor 1 receptor (CSF-1R/CD115) for development.…”

“…This reveals 3 major (CD103 + CD11b -, CD103 + CD11b + , and CD103 -CD11b + ) and one minor (CD103 -CD11b -) cDC subsets, all of which express the TF ZBTB46, are dependent on FLT3L for development in vivo and are derived from a pre-cDC precursor. 8,10,13 Importantly all four populations of CD103 …”

“…8,10,13,14 Thus each has the potential of initiating and regulating adaptive immune responses within LN.…”

TGF-β Signaling in Dendritic Cells Governs Colonic Homeostasis by Controlling Epithelial Differentiation and the Luminal Microbiota

“…Generally, intestinal CD11c + MHC class II + DCs can be divided into three major subsets; CD103 + CD11b 2 , CD103 + CD11b + , and CD103 2 CD11b + cells, and the functions of each subset are intensively analyzed in many studies (15,(28)(29)(30). In this study, we used CD11c-cre transgenic mice to examine the role of DCs and identified magnetically sorted CD11c + cells as DCs, although CD11c is reported to express on other immune cells such as CD8 + T cells in the intestine (31).…”

Galectin-9 Produced by Intestinal Epithelial Cells Enhances Aldehyde Dehydrogenase Activity in Dendritic Cells in a PI3K- and p38-Dependent Manner

“…-intestinal DC subsets have also been found to be critical in the induction of Th1 and Th17 type effector responses in the gut [4,5] .…”