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CD103+ CD11b+ Dendritic Cells Induce Th17 T Cells in Muc2-Deficient Mice with Extensively Spread Colitis.

Wenzel UA, Jonstrand C, Hansson GC, Wick MJ - PLoS ONE (2015)

Bottom Line: Mucus alterations are a feature of ulcerative colitis (UC) and can drive inflammation by compromising the mucosal barrier to luminal bacteria.The exact pathogenesis of UC remains unclear, but CD4+ T cells reacting to commensal antigens appear to contribute to pathology.These individuals also have increased numbers of CD103+ CD11b+ DCs in the distal colon.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology and the Mucosal Immunobiology and Vaccine Center (MIVAC), Institute of Biomedicine at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

ABSTRACT
Mucus alterations are a feature of ulcerative colitis (UC) and can drive inflammation by compromising the mucosal barrier to luminal bacteria. The exact pathogenesis of UC remains unclear, but CD4+ T cells reacting to commensal antigens appear to contribute to pathology. Given the unique capacity of dendritic cells (DCs) to activate naive T cells, colon DCs may activate pathogenic T cells and contribute to disease. Using Muc2-/- mice, which lack a functional mucus barrier and develop spontaneous colitis, we show that colitic animals have reduced colon CD103+ CD11b- DCs and increased CD103- CD11b+ phagocytes. Moreover, changes in colonic DC subsets and distinct cytokine patterns distinguish mice with distally localized colitis from mice with colitis spread proximally. Specifically, mice with proximally spread, but not distally contained, colitis have increased IL-1β, IL-6, IL-17, TNFα, and IFNγ combined with decreased IL-10 in the distal colon. These individuals also have increased numbers of CD103+ CD11b+ DCs in the distal colon. CD103+ CD11b+ DCs isolated from colitic but not noncolitic mice induced robust differentiation of Th17 cells but not Th1 cells ex vivo. In contrast, CD103- CD11b+ DCs from colitic Muc2-/- mice induced Th17 as well as Th1 differentiation. Thus, the local environment influences the capacity of intestinal DC subsets to induce T cell proliferation and differentiation, with CD103+ CD11b+ DCs inducing IL-17-producing T cells being a key feature of extensively spread colitis.

No MeSH data available.


Related in: MedlinePlus

Altered frequency of iMP populations in the colon of Muc2-/- mice.LP cells from proximal, middle and distal colon of Muc2+/- controls, Muc2-/-, and colitic Muc2-/- mice were analyzed by flow cytometry. (A) A representative dot plot of a Muc2+/- mouse showing gating of viable NK1.1-TCR-CD19-CD11c+MHC-II+ cells is depicted in the left two dot plots and further analysis of gated CD11c+MHC-II+ cells for expression of CD103 and CD11b for the indicated genotype of mouse is shown to the right. B-D depict the frequency of CD103+CD11b- "P1" DCs (B), CD103+CD11b+ "P2" DCs (C), and CD103-CD11b+ "P3" iMPs (D) among viable LP cells in the indicated gates. E-G show the absolute number of viable CD103+CD11b- "P1" DCs (E), CD103+CD11b+ “P2” DCs (F) and CD103-CD11b+ “P3” iMPs (G). Each symbol represents an individual mouse. For B-G results from the proximal (left column), middle (center column) and distal (right column) colon are shown. The mean of each group is indicated by the horizontal line. Segregating Muc2-/- mice into colitic and non-colitic is performed according to neutrophil influx in the respective colon segment. Data are from 12 independent experiments that analyzed 14–22 mice per group. Statistical significance between groups was assessed using the Kruskal-Wallis test followed by Dunn’s multiple comparison test.
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pone.0130750.g002: Altered frequency of iMP populations in the colon of Muc2-/- mice.LP cells from proximal, middle and distal colon of Muc2+/- controls, Muc2-/-, and colitic Muc2-/- mice were analyzed by flow cytometry. (A) A representative dot plot of a Muc2+/- mouse showing gating of viable NK1.1-TCR-CD19-CD11c+MHC-II+ cells is depicted in the left two dot plots and further analysis of gated CD11c+MHC-II+ cells for expression of CD103 and CD11b for the indicated genotype of mouse is shown to the right. B-D depict the frequency of CD103+CD11b- "P1" DCs (B), CD103+CD11b+ "P2" DCs (C), and CD103-CD11b+ "P3" iMPs (D) among viable LP cells in the indicated gates. E-G show the absolute number of viable CD103+CD11b- "P1" DCs (E), CD103+CD11b+ “P2” DCs (F) and CD103-CD11b+ “P3” iMPs (G). Each symbol represents an individual mouse. For B-G results from the proximal (left column), middle (center column) and distal (right column) colon are shown. The mean of each group is indicated by the horizontal line. Segregating Muc2-/- mice into colitic and non-colitic is performed according to neutrophil influx in the respective colon segment. Data are from 12 independent experiments that analyzed 14–22 mice per group. Statistical significance between groups was assessed using the Kruskal-Wallis test followed by Dunn’s multiple comparison test.

Mentions: We hypothesized that the local composition of iMPs, particularly those identified by CD103 and CD11b, could influence local inflammation. Therefore, the frequency of CD103+CD11b- (P1) and CD103+CD11b+ (P2) DC subsets in the colon LP was determined. In addition, the frequency of CD103-CD11b+ (P3) iMPs, which contains both conventional DCs and CD64+ monocyte-derived cells [2,9–11,14,24,25], was assessed. Analyzing the three colon segments separately showed that the percent of P1 DCs among MHCII+CD11c+ cells was reduced in all colon segments in colitic mice while their absolute number did not change (Fig 2A,2B and 2E). Neither the frequency nor number of P2 DCs was significantly altered in colon segments of colitic Muc2-/- mice (Fig 2A,2C and 2F). In contrast, the number of P3 iMPs increased in all colon segments (Fig 2A,2D and 2G). Thus, the spontaneous inflammation characterized by neutrophil infiltration in the colon LP of Muc2-/- mice corresponded with decreased frequency of P1 DCs and an increased number of P3 iMPs.


CD103+ CD11b+ Dendritic Cells Induce Th17 T Cells in Muc2-Deficient Mice with Extensively Spread Colitis.

Wenzel UA, Jonstrand C, Hansson GC, Wick MJ - PLoS ONE (2015)

Altered frequency of iMP populations in the colon of Muc2-/- mice.LP cells from proximal, middle and distal colon of Muc2+/- controls, Muc2-/-, and colitic Muc2-/- mice were analyzed by flow cytometry. (A) A representative dot plot of a Muc2+/- mouse showing gating of viable NK1.1-TCR-CD19-CD11c+MHC-II+ cells is depicted in the left two dot plots and further analysis of gated CD11c+MHC-II+ cells for expression of CD103 and CD11b for the indicated genotype of mouse is shown to the right. B-D depict the frequency of CD103+CD11b- "P1" DCs (B), CD103+CD11b+ "P2" DCs (C), and CD103-CD11b+ "P3" iMPs (D) among viable LP cells in the indicated gates. E-G show the absolute number of viable CD103+CD11b- "P1" DCs (E), CD103+CD11b+ “P2” DCs (F) and CD103-CD11b+ “P3” iMPs (G). Each symbol represents an individual mouse. For B-G results from the proximal (left column), middle (center column) and distal (right column) colon are shown. The mean of each group is indicated by the horizontal line. Segregating Muc2-/- mice into colitic and non-colitic is performed according to neutrophil influx in the respective colon segment. Data are from 12 independent experiments that analyzed 14–22 mice per group. Statistical significance between groups was assessed using the Kruskal-Wallis test followed by Dunn’s multiple comparison test.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4487685&req=5

pone.0130750.g002: Altered frequency of iMP populations in the colon of Muc2-/- mice.LP cells from proximal, middle and distal colon of Muc2+/- controls, Muc2-/-, and colitic Muc2-/- mice were analyzed by flow cytometry. (A) A representative dot plot of a Muc2+/- mouse showing gating of viable NK1.1-TCR-CD19-CD11c+MHC-II+ cells is depicted in the left two dot plots and further analysis of gated CD11c+MHC-II+ cells for expression of CD103 and CD11b for the indicated genotype of mouse is shown to the right. B-D depict the frequency of CD103+CD11b- "P1" DCs (B), CD103+CD11b+ "P2" DCs (C), and CD103-CD11b+ "P3" iMPs (D) among viable LP cells in the indicated gates. E-G show the absolute number of viable CD103+CD11b- "P1" DCs (E), CD103+CD11b+ “P2” DCs (F) and CD103-CD11b+ “P3” iMPs (G). Each symbol represents an individual mouse. For B-G results from the proximal (left column), middle (center column) and distal (right column) colon are shown. The mean of each group is indicated by the horizontal line. Segregating Muc2-/- mice into colitic and non-colitic is performed according to neutrophil influx in the respective colon segment. Data are from 12 independent experiments that analyzed 14–22 mice per group. Statistical significance between groups was assessed using the Kruskal-Wallis test followed by Dunn’s multiple comparison test.
Mentions: We hypothesized that the local composition of iMPs, particularly those identified by CD103 and CD11b, could influence local inflammation. Therefore, the frequency of CD103+CD11b- (P1) and CD103+CD11b+ (P2) DC subsets in the colon LP was determined. In addition, the frequency of CD103-CD11b+ (P3) iMPs, which contains both conventional DCs and CD64+ monocyte-derived cells [2,9–11,14,24,25], was assessed. Analyzing the three colon segments separately showed that the percent of P1 DCs among MHCII+CD11c+ cells was reduced in all colon segments in colitic mice while their absolute number did not change (Fig 2A,2B and 2E). Neither the frequency nor number of P2 DCs was significantly altered in colon segments of colitic Muc2-/- mice (Fig 2A,2C and 2F). In contrast, the number of P3 iMPs increased in all colon segments (Fig 2A,2D and 2G). Thus, the spontaneous inflammation characterized by neutrophil infiltration in the colon LP of Muc2-/- mice corresponded with decreased frequency of P1 DCs and an increased number of P3 iMPs.

Bottom Line: Mucus alterations are a feature of ulcerative colitis (UC) and can drive inflammation by compromising the mucosal barrier to luminal bacteria.The exact pathogenesis of UC remains unclear, but CD4+ T cells reacting to commensal antigens appear to contribute to pathology.These individuals also have increased numbers of CD103+ CD11b+ DCs in the distal colon.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology and the Mucosal Immunobiology and Vaccine Center (MIVAC), Institute of Biomedicine at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

ABSTRACT
Mucus alterations are a feature of ulcerative colitis (UC) and can drive inflammation by compromising the mucosal barrier to luminal bacteria. The exact pathogenesis of UC remains unclear, but CD4+ T cells reacting to commensal antigens appear to contribute to pathology. Given the unique capacity of dendritic cells (DCs) to activate naive T cells, colon DCs may activate pathogenic T cells and contribute to disease. Using Muc2-/- mice, which lack a functional mucus barrier and develop spontaneous colitis, we show that colitic animals have reduced colon CD103+ CD11b- DCs and increased CD103- CD11b+ phagocytes. Moreover, changes in colonic DC subsets and distinct cytokine patterns distinguish mice with distally localized colitis from mice with colitis spread proximally. Specifically, mice with proximally spread, but not distally contained, colitis have increased IL-1β, IL-6, IL-17, TNFα, and IFNγ combined with decreased IL-10 in the distal colon. These individuals also have increased numbers of CD103+ CD11b+ DCs in the distal colon. CD103+ CD11b+ DCs isolated from colitic but not noncolitic mice induced robust differentiation of Th17 cells but not Th1 cells ex vivo. In contrast, CD103- CD11b+ DCs from colitic Muc2-/- mice induced Th17 as well as Th1 differentiation. Thus, the local environment influences the capacity of intestinal DC subsets to induce T cell proliferation and differentiation, with CD103+ CD11b+ DCs inducing IL-17-producing T cells being a key feature of extensively spread colitis.

No MeSH data available.


Related in: MedlinePlus