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Interleukin 7 signaling in dendritic cells regulates the homeostatic proliferation and niche size of CD4+ T cells.

Guimond M, Veenstra RG, Grindler DJ, Zhang H, Cui Y, Murphy RD, Kim SY, Na R, Hennighausen L, Kurtulus S, Erman B, Matzinger P, Merchant MS, Mackall CL - Nat. Immunol. (2009)

Bottom Line: However, it is not known why CD4(+) T cells undergo less-efficient homeostatic proliferation than CD8(+) T cells do.This effect was mediated at least in part by IL-7-mediated downregulation of the expression of major histocompatibility complex class II on IL-7Ralpha(+) DCs.Our results indicate that IL-7Ralpha(+) DCs are regulators of the peripheral CD4(+) T cell niche and that IL-7 signals in DCs prevent uncontrolled CD4(+) T cell population expansion in vivo.

View Article: PubMed Central - PubMed

Affiliation: Pediatric Oncology Branch, National Cancer Institute, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.

ABSTRACT
Interleukin 7 (IL-7) and T cell antigen receptor signals have been proposed to be the main drivers of homeostatic T cell proliferation. However, it is not known why CD4(+) T cells undergo less-efficient homeostatic proliferation than CD8(+) T cells do. Here we show that systemic IL-7 concentrations increased during lymphopenia because of diminished use of IL-7 but that IL-7 signaling on IL-7 receptor-alpha-positive (IL-7Ralpha(+)) dendritic cells (DCs) in lymphopenic settings paradoxically diminished the homeostatic proliferation of CD4(+) T cells. This effect was mediated at least in part by IL-7-mediated downregulation of the expression of major histocompatibility complex class II on IL-7Ralpha(+) DCs. Our results indicate that IL-7Ralpha(+) DCs are regulators of the peripheral CD4(+) T cell niche and that IL-7 signals in DCs prevent uncontrolled CD4(+) T cell population expansion in vivo.

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IL-7 Signaling diminishes MHCII expression on APCs during lymphopenia. (a,b) APCs from mice expressing GFP under the control of the IL-7Rα promoter were analyzed by flow cytometry. *, P< 0.05. (c) Left, CD11b+CD11c-, CD11b+CD11c+ and CD11b-CD11c+ splenocytes in indicated mice were enumerated. Data show mean±s.e. Right, MHCII expression was measured on the designated splenocyte subsets from representative Il7r-/- (red shaded), and Rag-/- (blue line) mice. (d,e) MHCII expression on plasmacytoid DCs from indicated mice. (d) Representative histograms gated on CD11b-CD11c+B220+ cells. (e) MFI of MHCII expression. (n=6 mice/group) (f) MHCII expression on plasmacytoid DCs from indicated BM chimeras. These results are representative of three independent experiments.
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Figure 5: IL-7 Signaling diminishes MHCII expression on APCs during lymphopenia. (a,b) APCs from mice expressing GFP under the control of the IL-7Rα promoter were analyzed by flow cytometry. *, P< 0.05. (c) Left, CD11b+CD11c-, CD11b+CD11c+ and CD11b-CD11c+ splenocytes in indicated mice were enumerated. Data show mean±s.e. Right, MHCII expression was measured on the designated splenocyte subsets from representative Il7r-/- (red shaded), and Rag-/- (blue line) mice. (d,e) MHCII expression on plasmacytoid DCs from indicated mice. (d) Representative histograms gated on CD11b-CD11c+B220+ cells. (e) MFI of MHCII expression. (n=6 mice/group) (f) MHCII expression on plasmacytoid DCs from indicated BM chimeras. These results are representative of three independent experiments.

Mentions: Given findings implicating MHCII in CD4+ T cell homeostatic proliferation, and the evidence presented above demonstrating that IL-7 signaling on BM-derived cells regulates CD4+ T cell homeostatic proliferation, we sought to evaluate IL7Rα expression on DC subsets by enumerating IL-7Rα mRNA transcripts in electronically sorted splenocyte subpopulations. DCs expressed less IL-7Rα mRNA than T cells, but among the various DC subsets, CD11b- CD11c+ DCs expressed the most abundant IL-7Rα transcripts (Supplementary Fig. 5, online). Using splenocytes from mice expressing GFP under control of the IL-7Rα promoter, we confirmed that a sizable fraction of CD11b-CD11c+ DCs express IL-7Rα (Fig. 5a), and demonstrated that the majority of cells bearing the phenotype ascribed to plasmacytoid DCs (B220+CD11b-CD11c+ MHCII+) also express IL-7Rα (Fig. 5b). We next evaluated the effects of IL-7 signaling on MHCII expression in vivo on APCs. We observed diminished MHCII expression on CD11b+CD11c-, CD11b+CD11c+ and CD11b-CD11c+ cells in Rag1-/- compared to wild-type mice (Fig. 5c), with CD11b-CD11c+B220+ cells expressing the lowest amounts of MHCII. Modulation of MHC Class II expression was mediated by IL-7 signaling, as APCs from Il7r-/- and Il7-/- mice, which are as lymphopenic as Rag1-/- mice, expressed wild-type amounts of MHCII (Fig 5d,e). Furthermore, MHCII expression was restored on Rag1-/- DCs transplanted into Il7-/- but not Il7r-/- recipients (Fig. 5f).


Interleukin 7 signaling in dendritic cells regulates the homeostatic proliferation and niche size of CD4+ T cells.

Guimond M, Veenstra RG, Grindler DJ, Zhang H, Cui Y, Murphy RD, Kim SY, Na R, Hennighausen L, Kurtulus S, Erman B, Matzinger P, Merchant MS, Mackall CL - Nat. Immunol. (2009)

IL-7 Signaling diminishes MHCII expression on APCs during lymphopenia. (a,b) APCs from mice expressing GFP under the control of the IL-7Rα promoter were analyzed by flow cytometry. *, P< 0.05. (c) Left, CD11b+CD11c-, CD11b+CD11c+ and CD11b-CD11c+ splenocytes in indicated mice were enumerated. Data show mean±s.e. Right, MHCII expression was measured on the designated splenocyte subsets from representative Il7r-/- (red shaded), and Rag-/- (blue line) mice. (d,e) MHCII expression on plasmacytoid DCs from indicated mice. (d) Representative histograms gated on CD11b-CD11c+B220+ cells. (e) MFI of MHCII expression. (n=6 mice/group) (f) MHCII expression on plasmacytoid DCs from indicated BM chimeras. These results are representative of three independent experiments.
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Related In: Results  -  Collection

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Figure 5: IL-7 Signaling diminishes MHCII expression on APCs during lymphopenia. (a,b) APCs from mice expressing GFP under the control of the IL-7Rα promoter were analyzed by flow cytometry. *, P< 0.05. (c) Left, CD11b+CD11c-, CD11b+CD11c+ and CD11b-CD11c+ splenocytes in indicated mice were enumerated. Data show mean±s.e. Right, MHCII expression was measured on the designated splenocyte subsets from representative Il7r-/- (red shaded), and Rag-/- (blue line) mice. (d,e) MHCII expression on plasmacytoid DCs from indicated mice. (d) Representative histograms gated on CD11b-CD11c+B220+ cells. (e) MFI of MHCII expression. (n=6 mice/group) (f) MHCII expression on plasmacytoid DCs from indicated BM chimeras. These results are representative of three independent experiments.
Mentions: Given findings implicating MHCII in CD4+ T cell homeostatic proliferation, and the evidence presented above demonstrating that IL-7 signaling on BM-derived cells regulates CD4+ T cell homeostatic proliferation, we sought to evaluate IL7Rα expression on DC subsets by enumerating IL-7Rα mRNA transcripts in electronically sorted splenocyte subpopulations. DCs expressed less IL-7Rα mRNA than T cells, but among the various DC subsets, CD11b- CD11c+ DCs expressed the most abundant IL-7Rα transcripts (Supplementary Fig. 5, online). Using splenocytes from mice expressing GFP under control of the IL-7Rα promoter, we confirmed that a sizable fraction of CD11b-CD11c+ DCs express IL-7Rα (Fig. 5a), and demonstrated that the majority of cells bearing the phenotype ascribed to plasmacytoid DCs (B220+CD11b-CD11c+ MHCII+) also express IL-7Rα (Fig. 5b). We next evaluated the effects of IL-7 signaling on MHCII expression in vivo on APCs. We observed diminished MHCII expression on CD11b+CD11c-, CD11b+CD11c+ and CD11b-CD11c+ cells in Rag1-/- compared to wild-type mice (Fig. 5c), with CD11b-CD11c+B220+ cells expressing the lowest amounts of MHCII. Modulation of MHC Class II expression was mediated by IL-7 signaling, as APCs from Il7r-/- and Il7-/- mice, which are as lymphopenic as Rag1-/- mice, expressed wild-type amounts of MHCII (Fig 5d,e). Furthermore, MHCII expression was restored on Rag1-/- DCs transplanted into Il7-/- but not Il7r-/- recipients (Fig. 5f).

Bottom Line: However, it is not known why CD4(+) T cells undergo less-efficient homeostatic proliferation than CD8(+) T cells do.This effect was mediated at least in part by IL-7-mediated downregulation of the expression of major histocompatibility complex class II on IL-7Ralpha(+) DCs.Our results indicate that IL-7Ralpha(+) DCs are regulators of the peripheral CD4(+) T cell niche and that IL-7 signals in DCs prevent uncontrolled CD4(+) T cell population expansion in vivo.

View Article: PubMed Central - PubMed

Affiliation: Pediatric Oncology Branch, National Cancer Institute, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.

ABSTRACT
Interleukin 7 (IL-7) and T cell antigen receptor signals have been proposed to be the main drivers of homeostatic T cell proliferation. However, it is not known why CD4(+) T cells undergo less-efficient homeostatic proliferation than CD8(+) T cells do. Here we show that systemic IL-7 concentrations increased during lymphopenia because of diminished use of IL-7 but that IL-7 signaling on IL-7 receptor-alpha-positive (IL-7Ralpha(+)) dendritic cells (DCs) in lymphopenic settings paradoxically diminished the homeostatic proliferation of CD4(+) T cells. This effect was mediated at least in part by IL-7-mediated downregulation of the expression of major histocompatibility complex class II on IL-7Ralpha(+) DCs. Our results indicate that IL-7Ralpha(+) DCs are regulators of the peripheral CD4(+) T cell niche and that IL-7 signals in DCs prevent uncontrolled CD4(+) T cell population expansion in vivo.

Show MeSH
Related in: MedlinePlus