Dendritic cell subsets in the intestinal lamina propria: ontogeny and function

Abstract

The intestinal mucosa is exposed to large amounts of foreign antigen (Ag) derived from commensal bacteria, dietary Ags, and intestinal pathogens. Dendritic cells (DCs) are believed to be involved in the induction of tolerance to harmless Ags and in mounting protective immune responses to pathogens and, as such, to play key roles in regulating intestinal immune homeostasis. The characterization of classical DCs (cDCs) in the intestinal lamina propria has been under intense investigation in recent years but the use of markers (including CD11c, CD11b, MHC class II), which are also expressed by intestinal MΦs, has led to some controversy regarding their definition. Here we review recent studies that help to distinguish cDCs subsets from monocyte-derived cells in the intestinal mucosa. We address the phenotype and ontogeny of these cDC subsets and highlight recent findings indicating that these subsets play distinct roles in the regulation of mucosal immune responses in vivo.

Keywords: Antigen tolerance; Dendritic cells; Intestine; Lamina propria; Mucosa.

Figure 1

Phenotypic characterization of MPs in the SI LP. Representative flow cytometry plots of MPs in the steady-state SI LP of CX3CR1^gfp/wt mice (PPs are removed prior to analysis). Leukocytes are identified among live cells as CD45⁺. Monocytes/ MΦs are identified among the CD11c⁺MHCII⁺ cells as CD64⁺ cells, and cDCs are identified as CD64⁻ cells. cDCs can be separated into two major subsets of CD103⁺ cells: CD103⁺CD11b⁺ cDCs and CD103⁺CD11b⁻ cDCs, both of which are CX3CR1^lo/−. In addition there is a minor population of CD103⁻ cDCs that express variable levels of CD11b, the majority of which are CX3CR1^int. The CD11b⁻ cells within this latter population are not present in intestinal preparations of RORγt^−/− mice, which lack PPs and ILFs, suggesting they derive from GALT and not intestinal LP .

Figure 2

Overview of intestinal MPs. Ly6C^hi monocytes and cDC precursors seed the intestine from the blood where they give rise to distinct populations of MPs. cDC precursors, but not monocytes, give rise to CD103⁺CD11b⁻ and CD103⁺CD11b⁺ cDCs whose development/maintenance depends on distinct transcription factors. CD103⁺CD11b⁻ cDC are dependent on BatF3, IRF8, and Id2; CD103⁺CD11b⁺ cDC on IRF4 and Notch2. In the absence of IRF4 (ΔIRF4) CD103⁺CD11b⁺ cDC survival is compromised. It is currently unclear whether cDC precursors entering the intestine are precommitted to developing into one or other of these populations or whether the same precursor can develop into either subset depending on the signals it receives within the intestinal environment. In addition to CD103⁺ cDCs there is a minor population of CD103⁻CD64⁻CD11b⁺ cells in intestinal LP ,, which likely represent bona fide cDCs (see main text). In contrast to CD64⁻ cDCs, CD64⁺ MΦs develop from Ly6C^hi monocytes through a series of intermediate steps during which they lose the expression of Ly6C and gain expression of MHC class II ,.