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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

Local accumulation of neutrophils in the colon of Muc2-/- mice.LP cells from proximal, middle or distal colon sections of Muc2-/- and Muc2+/- littermates were analyzed by flow cytometry. (A) Viable neutrophils were identified as 7AAD-MHCII-CD11b+Ly6G+ cells. The numbers represent the percent of cells in the indicated gate. (B) The frequency of neutrophils among viable LP cells for all mice examined is shown. The dashed line indicates the “cut off” value of 0.36%[23]). (C) The frequency of CD11b+MHC-/low cells among viable LP cells of all mice examined is depicted. Each symbol represents an individual mouse and the horizontal line indicates the mean. Results are from 12 independent experiments with a total of 14–22 mice per group. Statistical significance was assessed using the Kruskal-Wallis test followed by Dunn’s multiple comparison test.
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pone.0130750.g001: Local accumulation of neutrophils in the colon of Muc2-/- mice.LP cells from proximal, middle or distal colon sections of Muc2-/- and Muc2+/- littermates were analyzed by flow cytometry. (A) Viable neutrophils were identified as 7AAD-MHCII-CD11b+Ly6G+ cells. The numbers represent the percent of cells in the indicated gate. (B) The frequency of neutrophils among viable LP cells for all mice examined is shown. The dashed line indicates the “cut off” value of 0.36%[23]). (C) The frequency of CD11b+MHC-/low cells among viable LP cells of all mice examined is depicted. Each symbol represents an individual mouse and the horizontal line indicates the mean. Results are from 12 independent experiments with a total of 14–22 mice per group. Statistical significance was assessed using the Kruskal-Wallis test followed by Dunn’s multiple comparison test.

Mentions: Recently, we demonstrated that spontaneous intestinal inflammation in Muc2-/- mice is restricted to the colon and shares features of human ulcerative colitis [23]. In this study, Muc2-/- mice were placed into colitic versus non-colitic groups based on neutrophil influx in the whole colon, using a threshold of > 0.36% neutrophils among viable LP cells to define colitic mice [23]. Because human ulcerative colitis proceeds proximally from rectum to cecum, we hypothesized that infiltration of neutrophils in Muc2-/- mice would be more prominent in the distal than the proximal colon. Hence, we analyzed neutrophil infiltration into the LP of proximal, middle and distal colon segments of Muc2+/- and Muc2-/- mice. This revealed that 5 of 35 Muc2-/- mice had > 0.36% neutrophil in the proximal colon LP and were thus classified as colitic in this colon segment (Fig 1A and 1B). In the distal colon, however, these 5 mice plus 16 additional Muc2-/- mice, but no Muc2+/- mice, had > 0.36% neutrophils (Fig 1A and 1B). No change in neutrophil frequency was apparent among small intestinal LP cells regardless of the neutrophil frequency in any of the colon segments of the same individual or age of the mice (data not shown and [23]). In addition, CD11bhiMHCII-/low cells were increased in mice classified as colitic based on increased neutrophils, particularly in the distal colon (Fig 1A and 1C). Thus, spontaneous colitis in Muc2-/- mice monitored by neutrophil infiltration is most frequently observed in the distal colon and correlates with the influx of CD11bhiMHCII-/low cells.


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)

Local accumulation of neutrophils in the colon of Muc2-/- mice.LP cells from proximal, middle or distal colon sections of Muc2-/- and Muc2+/- littermates were analyzed by flow cytometry. (A) Viable neutrophils were identified as 7AAD-MHCII-CD11b+Ly6G+ cells. The numbers represent the percent of cells in the indicated gate. (B) The frequency of neutrophils among viable LP cells for all mice examined is shown. The dashed line indicates the “cut off” value of 0.36%[23]). (C) The frequency of CD11b+MHC-/low cells among viable LP cells of all mice examined is depicted. Each symbol represents an individual mouse and the horizontal line indicates the mean. Results are from 12 independent experiments with a total of 14–22 mice per group. Statistical significance 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.g001: Local accumulation of neutrophils in the colon of Muc2-/- mice.LP cells from proximal, middle or distal colon sections of Muc2-/- and Muc2+/- littermates were analyzed by flow cytometry. (A) Viable neutrophils were identified as 7AAD-MHCII-CD11b+Ly6G+ cells. The numbers represent the percent of cells in the indicated gate. (B) The frequency of neutrophils among viable LP cells for all mice examined is shown. The dashed line indicates the “cut off” value of 0.36%[23]). (C) The frequency of CD11b+MHC-/low cells among viable LP cells of all mice examined is depicted. Each symbol represents an individual mouse and the horizontal line indicates the mean. Results are from 12 independent experiments with a total of 14–22 mice per group. Statistical significance was assessed using the Kruskal-Wallis test followed by Dunn’s multiple comparison test.
Mentions: Recently, we demonstrated that spontaneous intestinal inflammation in Muc2-/- mice is restricted to the colon and shares features of human ulcerative colitis [23]. In this study, Muc2-/- mice were placed into colitic versus non-colitic groups based on neutrophil influx in the whole colon, using a threshold of > 0.36% neutrophils among viable LP cells to define colitic mice [23]. Because human ulcerative colitis proceeds proximally from rectum to cecum, we hypothesized that infiltration of neutrophils in Muc2-/- mice would be more prominent in the distal than the proximal colon. Hence, we analyzed neutrophil infiltration into the LP of proximal, middle and distal colon segments of Muc2+/- and Muc2-/- mice. This revealed that 5 of 35 Muc2-/- mice had > 0.36% neutrophil in the proximal colon LP and were thus classified as colitic in this colon segment (Fig 1A and 1B). In the distal colon, however, these 5 mice plus 16 additional Muc2-/- mice, but no Muc2+/- mice, had > 0.36% neutrophils (Fig 1A and 1B). No change in neutrophil frequency was apparent among small intestinal LP cells regardless of the neutrophil frequency in any of the colon segments of the same individual or age of the mice (data not shown and [23]). In addition, CD11bhiMHCII-/low cells were increased in mice classified as colitic based on increased neutrophils, particularly in the distal colon (Fig 1A and 1C). Thus, spontaneous colitis in Muc2-/- mice monitored by neutrophil infiltration is most frequently observed in the distal colon and correlates with the influx of CD11bhiMHCII-/low cells.

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