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Proinflammatory microenvironments within the intestine regulate the differentiation of tissue-resident CD8⁺ T cells responding to infection.

Bergsbaken T, Bevan MJ - Nat. Immunol. (2015)

Bottom Line: CD103(-) T cells did not require transforming growth factor-β (TGF-β) signaling but were true resident memory cells.Unlike CD103(+)CD8(+) T cells, which were TGF-β dependent and were scattered in the tissue, CD103(-)CD8(+) T cells clustered with CD4(+) T cells and CX3CR1(+) macrophages and/or dendritic cells around areas of bacterial infection.CXCR3-dependent recruitment of cells to inflamed areas was critical for development of the CD103(-) population and pathogen clearance.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology and Howard Hughes Medical Institute, University of Washington, Seattle, Washington, USA.

ABSTRACT
We report that oral infection with Yersinia pseudotuberculosis results in the development of two distinct populations of pathogen-specific CD8(+) tissue-resident memory T cells (TRM cells) in the lamina propria. CD103(-) T cells did not require transforming growth factor-β (TGF-β) signaling but were true resident memory cells. Unlike CD103(+)CD8(+) T cells, which were TGF-β dependent and were scattered in the tissue, CD103(-)CD8(+) T cells clustered with CD4(+) T cells and CX3CR1(+) macrophages and/or dendritic cells around areas of bacterial infection. CXCR3-dependent recruitment of cells to inflamed areas was critical for development of the CD103(-) population and pathogen clearance. Our studies have identified the 'preferential' development of CD103(-) TRM cells in inflammatory microenvironments within the lamina propria and suggest that this subset has a critical role in controlling infection.

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Yptb-OVA induced clusters contain T cells and CX3CR1+ macrophages and/or DCs but not B cells. OT-I cells were transferred into C57BL/6 (a,b) or Cx3cr1gfp/+ (CX3CR1-GFP) (e) mice and one day later mice were orally infected with Yptb-OVA. On day 9 post infection, the distribution of OT-I cells and other immune cells in the ileum was analyzed by immunohistochemistry. OT-I (green) localization near (a) B220+ cells (purple) and (b) CD4 and CD8 T cells (red and blue, respectively). Scale bars equal 25 μm. Representative data from 3-5 mice (a,b). (c,d) CX3CR1-GFP mice were infected with Yptb-OVA and on day 7 post infection LP cells were isolated and compared to naive controls. (c) Flow cytometry analysis of populations by expression of MHC class II, CD11c, CD11b, CD103, and CX3CR1-GFP. (d) Cell populations are graphed as a percent of total MHC class II+ LP cells; data are means and SDs pooled from 2 experiments with 4-7 mice/group. *p<0.05 (unpaired t-test). (e) CD90.1 OT-I (red) localization near CD11c (blue) and CX3CR1-GFP expressing cells. Scale bars equal 25 μm. Representative data from 3 mice.
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Figure 5: Yptb-OVA induced clusters contain T cells and CX3CR1+ macrophages and/or DCs but not B cells. OT-I cells were transferred into C57BL/6 (a,b) or Cx3cr1gfp/+ (CX3CR1-GFP) (e) mice and one day later mice were orally infected with Yptb-OVA. On day 9 post infection, the distribution of OT-I cells and other immune cells in the ileum was analyzed by immunohistochemistry. OT-I (green) localization near (a) B220+ cells (purple) and (b) CD4 and CD8 T cells (red and blue, respectively). Scale bars equal 25 μm. Representative data from 3-5 mice (a,b). (c,d) CX3CR1-GFP mice were infected with Yptb-OVA and on day 7 post infection LP cells were isolated and compared to naive controls. (c) Flow cytometry analysis of populations by expression of MHC class II, CD11c, CD11b, CD103, and CX3CR1-GFP. (d) Cell populations are graphed as a percent of total MHC class II+ LP cells; data are means and SDs pooled from 2 experiments with 4-7 mice/group. *p<0.05 (unpaired t-test). (e) CD90.1 OT-I (red) localization near CD11c (blue) and CX3CR1-GFP expressing cells. Scale bars equal 25 μm. Representative data from 3 mice.

Mentions: The intestinal distribution of CD103+ and CD103– OT-I T cells during Yptb-OVA infection was distinct, and we sought to define the local immune environment in clusters that contained CD103– CD8 T cells. Isolated lymphoid follicles (ILFs) in the gut are generated soon after birth in response to microbial colonization and mature ILFs contain B cells, CD11c+ dendritic cells (DCs), and a small number of lymphoid tissue inducer cells23. The M cells that overlie these structures are a major portal of Yptb entry into the intestinal tissue24,25, and pathogens such as Salmonella have been shown to preferentially invade ILFs26. Therefore, we hypothesized that ILFs may support Yptb invasion and/or replication and CD8 T cell clustering. To examine this, intestinal tissue sections from Yptb-OVA infected mice were stained with anti-B220 antibodies to identify B cells and colocalization with OT-I cells was assessed. We occasionally observed a small number of OT-I T cells associating with clustered B220+ cells characteristic of ILFs (Fig. 5a), but OT-I T cell clusters contained few if any B220+ cells (Supplementary Fig. 5). These data indicate OT-I T cell clusters are not formed in or around ILFs during Yptb-OVA infection, although OT-I cells are not excluded from these structures.


Proinflammatory microenvironments within the intestine regulate the differentiation of tissue-resident CD8⁺ T cells responding to infection.

Bergsbaken T, Bevan MJ - Nat. Immunol. (2015)

Yptb-OVA induced clusters contain T cells and CX3CR1+ macrophages and/or DCs but not B cells. OT-I cells were transferred into C57BL/6 (a,b) or Cx3cr1gfp/+ (CX3CR1-GFP) (e) mice and one day later mice were orally infected with Yptb-OVA. On day 9 post infection, the distribution of OT-I cells and other immune cells in the ileum was analyzed by immunohistochemistry. OT-I (green) localization near (a) B220+ cells (purple) and (b) CD4 and CD8 T cells (red and blue, respectively). Scale bars equal 25 μm. Representative data from 3-5 mice (a,b). (c,d) CX3CR1-GFP mice were infected with Yptb-OVA and on day 7 post infection LP cells were isolated and compared to naive controls. (c) Flow cytometry analysis of populations by expression of MHC class II, CD11c, CD11b, CD103, and CX3CR1-GFP. (d) Cell populations are graphed as a percent of total MHC class II+ LP cells; data are means and SDs pooled from 2 experiments with 4-7 mice/group. *p<0.05 (unpaired t-test). (e) CD90.1 OT-I (red) localization near CD11c (blue) and CX3CR1-GFP expressing cells. Scale bars equal 25 μm. Representative data from 3 mice.
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Figure 5: Yptb-OVA induced clusters contain T cells and CX3CR1+ macrophages and/or DCs but not B cells. OT-I cells were transferred into C57BL/6 (a,b) or Cx3cr1gfp/+ (CX3CR1-GFP) (e) mice and one day later mice were orally infected with Yptb-OVA. On day 9 post infection, the distribution of OT-I cells and other immune cells in the ileum was analyzed by immunohistochemistry. OT-I (green) localization near (a) B220+ cells (purple) and (b) CD4 and CD8 T cells (red and blue, respectively). Scale bars equal 25 μm. Representative data from 3-5 mice (a,b). (c,d) CX3CR1-GFP mice were infected with Yptb-OVA and on day 7 post infection LP cells were isolated and compared to naive controls. (c) Flow cytometry analysis of populations by expression of MHC class II, CD11c, CD11b, CD103, and CX3CR1-GFP. (d) Cell populations are graphed as a percent of total MHC class II+ LP cells; data are means and SDs pooled from 2 experiments with 4-7 mice/group. *p<0.05 (unpaired t-test). (e) CD90.1 OT-I (red) localization near CD11c (blue) and CX3CR1-GFP expressing cells. Scale bars equal 25 μm. Representative data from 3 mice.
Mentions: The intestinal distribution of CD103+ and CD103– OT-I T cells during Yptb-OVA infection was distinct, and we sought to define the local immune environment in clusters that contained CD103– CD8 T cells. Isolated lymphoid follicles (ILFs) in the gut are generated soon after birth in response to microbial colonization and mature ILFs contain B cells, CD11c+ dendritic cells (DCs), and a small number of lymphoid tissue inducer cells23. The M cells that overlie these structures are a major portal of Yptb entry into the intestinal tissue24,25, and pathogens such as Salmonella have been shown to preferentially invade ILFs26. Therefore, we hypothesized that ILFs may support Yptb invasion and/or replication and CD8 T cell clustering. To examine this, intestinal tissue sections from Yptb-OVA infected mice were stained with anti-B220 antibodies to identify B cells and colocalization with OT-I cells was assessed. We occasionally observed a small number of OT-I T cells associating with clustered B220+ cells characteristic of ILFs (Fig. 5a), but OT-I T cell clusters contained few if any B220+ cells (Supplementary Fig. 5). These data indicate OT-I T cell clusters are not formed in or around ILFs during Yptb-OVA infection, although OT-I cells are not excluded from these structures.

Bottom Line: CD103(-) T cells did not require transforming growth factor-β (TGF-β) signaling but were true resident memory cells.Unlike CD103(+)CD8(+) T cells, which were TGF-β dependent and were scattered in the tissue, CD103(-)CD8(+) T cells clustered with CD4(+) T cells and CX3CR1(+) macrophages and/or dendritic cells around areas of bacterial infection.CXCR3-dependent recruitment of cells to inflamed areas was critical for development of the CD103(-) population and pathogen clearance.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology and Howard Hughes Medical Institute, University of Washington, Seattle, Washington, USA.

ABSTRACT
We report that oral infection with Yersinia pseudotuberculosis results in the development of two distinct populations of pathogen-specific CD8(+) tissue-resident memory T cells (TRM cells) in the lamina propria. CD103(-) T cells did not require transforming growth factor-β (TGF-β) signaling but were true resident memory cells. Unlike CD103(+)CD8(+) T cells, which were TGF-β dependent and were scattered in the tissue, CD103(-)CD8(+) T cells clustered with CD4(+) T cells and CX3CR1(+) macrophages and/or dendritic cells around areas of bacterial infection. CXCR3-dependent recruitment of cells to inflamed areas was critical for development of the CD103(-) population and pathogen clearance. Our studies have identified the 'preferential' development of CD103(-) TRM cells in inflammatory microenvironments within the lamina propria and suggest that this subset has a critical role in controlling infection.

Show MeSH
Related in: MedlinePlus