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. 2008 Sep 1;205(9):2139-49.
doi: 10.1084/jem.20080414. Epub 2008 Aug 18.

Small intestinal CD103+ dendritic cells display unique functional properties that are conserved between mice and humans

Elin Jaensson  1 , Heli Uronen-Hansson, Oliver Pabst, Bertus Eksteen, Jiong Tian, Janine L Coombes, Pia-Lena Berg, Thomas Davidsson, Fiona Powrie, Bengt Johansson-Lindbom, William W Agace
Affiliations

Small intestinal CD103+ dendritic cells display unique functional properties that are conserved between mice and humans

Elin Jaensson et al. J Exp Med. .

Abstract

A functionally distinct subset of CD103(+) dendritic cells (DCs) has recently been identified in murine mesenteric lymph nodes (MLN) that induces enhanced FoxP3(+) T cell differentiation, retinoic acid receptor signaling, and gut-homing receptor (CCR9 and alpha4beta7) expression in responding T cells. We show that this function is specific to small intestinal lamina propria (SI-LP) and MLN CD103(+) DCs. CD103(+) SI-LP DCs appeared to derive from circulating DC precursors that continually seed the SI-LP. BrdU pulse-chase experiments suggested that most CD103(+) DCs do not derive from a CD103(-) SI-LP DC intermediate. The majority of CD103(+) MLN DCs appear to represent a tissue-derived migratory population that plays a central role in presenting orally derived soluble antigen to CD8(+) and CD4(+) T cells. In contrast, most CD103(-) MLN DCs appear to derive from blood precursors, and these cells could proliferate within the MLN and present systemic soluble antigen. Critically, CD103(+) DCs with similar phenotype and functional properties were present in human MLN, and their selective ability to induce CCR9 was maintained by CD103(+) MLN DCs isolated from SB Crohn's patients. Thus, small intestinal CD103(+) DCs represent a potential novel target for regulating human intestinal inflammatory responses.

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Figures

Figure 1.
Figure 1.
Small intestinal LP and MLN CD103+ DCs are unique in their capacity to efficiently induce CCR9 on responding T cells. (A) Percentage of DCs (MHC class II+CD11c+) expressing CD103 in indicated organs. Results are the mean and SD from three to eight independent experiments (two to five mice per experiment). (B and C) CD103+ and CD103− DCs were sorted from the indicated organs by FACS, pulsed with 2 nM (B and C) or 200 pM (C) pOVA257–264, and incubated with OT-I cells. CCR9 expression on responding OT-I cells was assessed after 6 d by flow cytometry. Representative FACS plots (B) and mean and SD (C) of the indicated number of separate experiments are shown. (D and E) CD103+ and CD103− DCs were sorted from the indicated organs by FACS, pulsed with 200 pM pOVA257–264, and incubated with DR5.OT-I cells. Luciferase activity was determined after 22 h of culture. Data are normalized to the luciferase expression observed in CD103+ MLN DC:DR5.OT-I cell cultures within each experiment. −, DR5.OT-I cells alone. Results are the mean and SD of the indicated number of separate experiments. (E) Luciferase activity was blocked when 1 μM of the pan-RAR antagonist LE540 was added to MLN DC-T cell cultures. Results are the mean and SD of three experiments. *, P < 0.05; **, P < 0.01; ***, P < 0.001 (compared with CD103+ MLN DCs). LDLN, Lung draining LN; Co-LP, colonic LP.
Figure 2.
Figure 2.
CD103 is not required for imprinting MLN DCs with the ability to induce CCR9 on responding T cells. 105 MLN DCs from WT and CD103−/− BALB/c mice were cultured together with 2 × 105 CFSE-labeled DO11.10 SCID CD4+ cells, and OVA and expression of CCR9 and α4β7 was assessed 6 (experiment 1 [Expt. 1]) or 7 (experiment 2) d later. (A) Representative FACS plots. (B) Mean and SD of three mice per group for both experiments.
Figure 3.
Figure 3.
Turnover of SI-LP and MLN CD103+ and CD103− DC. (A) Mice were injected i.p. with 2 mg BrdU, and the percentage of BrdU+ CD103+ and CD103− DCs (MHC class II+CD11c+) in the SI-LP and MLN was determined by flow cytometry at the times indicated. Results are the mean and SD of three to seven independent experiments with two mice in each time point except the 72-h time point, which was performed once. (B) BrdU and Ki67 staining on SI-LP and MLN CD103+ and CD103− DCs (MHC class II+ CD11c+) was assessed by flow cytometry 3 and 24 h after BrdU injection. Plots are from one representative experiment of three performed. (C) SI from CD45.2+ mice (graft) was transplanted into CD45.1+ recipients (host) as previously described (32). At days 6 and 45, host and graft intestine were sectioned and stained with antibodies to CD45.2 (red), CD11c (blue), and MHC class II (green). Immunohistochemistry of the 45-d graft is shown. Arrows point to host-derived CD45.2−MHC class IIhiCD11c+ DCs. Bar, 25 μm. The graph is percentage of host-derived (CD45.2 negative) CD11c+MHC class IIhi cells in graft and host small intestinal villus. Results are mean and SD (n = 3 mice per group).
Figure 4.
Figure 4.
Localization of CD103+ and CD103− MHC class II+CD11c+ cells within the small intestinal mucosa. (A and B) Expression of CD103 by DCs in small intestinal villus and SILT. (A) Images show overlays of CD103 (red) in combination with CD11c (blue) and MHC class II (green), with insets showing DAPI staining. Arrows point toward MHC class IIhiCD11c+ DCs coexpressing CD103. Bars, 50 μm. (B) The graph is percentage of MHC class IIhiCD11c+ cells in SI villus or dome region of SILT that express CD103. Results are mean and SD (n = 5 mice per group). ***, P < 0.001.
Figure 5.
Figure 5.
CD103+ DCs present orally administered soluble antigen to CD4+ and CD8+ T cells. (A and B) Mice received PBS 5 mg OVA i.p., or 50 mg orally, and MLN were harvested after 17 h. 105 CD103+ and CD103− MLN DCs were isolated by cell sorting and cocultured with 2 × 105 CFSE-labeled OT-I or OT-II cells. (A) CFSE profile of OT-I and OT-II cells 3.5 d after coculture with indicated DCs. Data are representative of three to five separate experiments using MLN DCs isolated from 15–20 pooled mice per group. (B) Expression of CCR9 and α4β7 was analyzed by FACS after 3.5 d in coculture. The graph shows mean and SEM from five independent experiments. *, P < 0.05 (when comparing CD103+ and CD103− DC–primed cultures).
Figure 6.
Figure 6.
Phenotypic characterization of human CD103+ and CD103− MLN DCs. (A) Human MLN section stained with anti–DC-LAMP (FITC), CD103 (Cy3), and IgG (Cy5) antibody to identify B cell follicles for orientation in the LN. CD103+ DCs (yellow). Bar, 100 μm. (B) Percent of DCs expressing CD103 in normal and Crohn's MLN, as determined by flow cytometry using the DC gatings described in Fig. S2 A (available at http://www.jem.org/cgi/content/full/jem.20080414/DC1). Filled squares, normal MLN (bladder reconstruction patients; n = 9); open squares, colon cancer patients (n = 4); triangles, SB Crohn's patients (n = 6). (C and D) CD40 and CD83 expression on CD103+ and CD103− normal MLN DCs using the gatings described in Fig. S2 A (available at http://www.jem.org/cgi/content/full/jem.20080414/DC1). Representative FACS plots (C) and mean and SD (D) of three (CD83) or four (CD40) independent experiments. **, P < 0.01. Results are normalized within each experiment to the percent expression on CD103+ DCs.
Figure 7.
Figure 7.
Human MLN CD103+ DCs efficiently induce CCR9 on responding T cells. (A–C) CCR9 and α4β7 expression on CD8+ T cells primed with CD103+ or CD103− DCs from normal (A–C) or SB Crohn's (B and C) MLN. DCs were sorted as described in Materials and methods and Fig. S2 B (available at http://www.jem.org/cgi/content/full/jem.20080414/DC1). (A) Representative flow cytometry plots. (B) CCR9 expression on T cells stimulated with CD103+ (empty symbols) or CD103− MLN DCs (filled symbols). Each symbol represents a separate experiment and horizontal line represents the mean value. Boxes in A show the gates that were used to assess CCR9 expression. (C) α4β7 expression on T cells stimulated with CD103+ or CD103− MLN DCs. Normal, mean and SD of four experiments; Crohn's, mean of two experiments. Because α4β7 is induced in a cell cycle–dependent manner (12, 13, 54), α4β7 expression was assessed on cells that had divided six to nine times (arrows in A). (D) Gut-homing receptor induction by CD103+ DCs from normal human MLN was inhibited by addition of 1 μM of the pan-RAR antagonist LE540 to the cell cultures. Results are mean and SD of four separate experiments. ***, P < 0.001.
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