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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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Stromal cell-derived IL-7 regulates DC IL-7 production within the lymphoid microenvironment. (a) IL-7 mRNA expression in splenocytes from indicated mice was measured by RT-PCR. Horizontal lines indicate mean, and each dot represents an individual mouse. 6 to 10 individual mice were analyzed and the experiment was done twice *, P<0.05 and **, P<0.005. (b) IL-7 and IL-7Rα mRNA expression in electronically sorted CD11b-CD11c+ and CD11b+CD11c- cells from pooled wild-type mice. Results are representative of 2 independent experiments. (c) IL-7 (green) and CD45 (red) expression in spleens of indicated mice, as measured by immunofluorescence. Results are representative of 2 independent experiments.
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Figure 6: Stromal cell-derived IL-7 regulates DC IL-7 production within the lymphoid microenvironment. (a) IL-7 mRNA expression in splenocytes from indicated mice was measured by RT-PCR. Horizontal lines indicate mean, and each dot represents an individual mouse. 6 to 10 individual mice were analyzed and the experiment was done twice *, P<0.05 and **, P<0.005. (b) IL-7 and IL-7Rα mRNA expression in electronically sorted CD11b-CD11c+ and CD11b+CD11c- cells from pooled wild-type mice. Results are representative of 2 independent experiments. (c) IL-7 (green) and CD45 (red) expression in spleens of indicated mice, as measured by immunofluorescence. Results are representative of 2 independent experiments.

Mentions: In addition to the effects of IL-7 signaling on MHCII expression, it remains possible that other effects of IL-7Rα signaling on DCs contribute to the diminished CD4+ T cell homeostatic proliferation observed in the presence of high levels of stromal cell-derived IL-7. Given that IL-7 production exclusively by BM-derived cells is necessary and sufficient to sustain CD4+ T cell homeostatic proliferation in Il7-/- recipient mice, we postulated that IL-7 production by DCs themselves may be physiologically relevant in vivo. Therefore, we sought to determine whether IL-7 signaling on DCs regulates IL-7 production by DCs as it does on stromal cells. Similar to results obtained with stromal cell preparations, IL-7 mRNA was diminished in splenocytes from Rag1-/- mice (Fig. 6a) compared to splenocytes from wild-type or Il7r-/- mice, demonstrating that IL-7Rα-mediated feedback also regulates non-stromal cell derived IL-7 production. Among IL-7-producing DC subsets, we noted an inverse relationship between IL-7Rα expression and IL-7 production, such that IL-7 production was lower in the IL-7Rα+CD11b-CD11c+ subset than in the IL-7Rα-/loCD11b+CD11c+ subset (Fig. 6b and Supplementary Fig. 6b, online). We noted higher numbers of cells producing more abundant IL-7 within the DC region of the spleen of Il7r-/- compared with Rag1-/- or wild-type mice (Fig. 6c). Thus, IL-7Rα signaling facilitates downregulation of MHCII expression and IL-7 production in DCs; these feedback loops could explain the detrimental effects of high systemic IL-7 quantities on CD4+ T cell homeostatic proliferation.


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)

Stromal cell-derived IL-7 regulates DC IL-7 production within the lymphoid microenvironment. (a) IL-7 mRNA expression in splenocytes from indicated mice was measured by RT-PCR. Horizontal lines indicate mean, and each dot represents an individual mouse. 6 to 10 individual mice were analyzed and the experiment was done twice *, P<0.05 and **, P<0.005. (b) IL-7 and IL-7Rα mRNA expression in electronically sorted CD11b-CD11c+ and CD11b+CD11c- cells from pooled wild-type mice. Results are representative of 2 independent experiments. (c) IL-7 (green) and CD45 (red) expression in spleens of indicated mice, as measured by immunofluorescence. Results are representative of 2 independent experiments.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2713006&req=5

Figure 6: Stromal cell-derived IL-7 regulates DC IL-7 production within the lymphoid microenvironment. (a) IL-7 mRNA expression in splenocytes from indicated mice was measured by RT-PCR. Horizontal lines indicate mean, and each dot represents an individual mouse. 6 to 10 individual mice were analyzed and the experiment was done twice *, P<0.05 and **, P<0.005. (b) IL-7 and IL-7Rα mRNA expression in electronically sorted CD11b-CD11c+ and CD11b+CD11c- cells from pooled wild-type mice. Results are representative of 2 independent experiments. (c) IL-7 (green) and CD45 (red) expression in spleens of indicated mice, as measured by immunofluorescence. Results are representative of 2 independent experiments.
Mentions: In addition to the effects of IL-7 signaling on MHCII expression, it remains possible that other effects of IL-7Rα signaling on DCs contribute to the diminished CD4+ T cell homeostatic proliferation observed in the presence of high levels of stromal cell-derived IL-7. Given that IL-7 production exclusively by BM-derived cells is necessary and sufficient to sustain CD4+ T cell homeostatic proliferation in Il7-/- recipient mice, we postulated that IL-7 production by DCs themselves may be physiologically relevant in vivo. Therefore, we sought to determine whether IL-7 signaling on DCs regulates IL-7 production by DCs as it does on stromal cells. Similar to results obtained with stromal cell preparations, IL-7 mRNA was diminished in splenocytes from Rag1-/- mice (Fig. 6a) compared to splenocytes from wild-type or Il7r-/- mice, demonstrating that IL-7Rα-mediated feedback also regulates non-stromal cell derived IL-7 production. Among IL-7-producing DC subsets, we noted an inverse relationship between IL-7Rα expression and IL-7 production, such that IL-7 production was lower in the IL-7Rα+CD11b-CD11c+ subset than in the IL-7Rα-/loCD11b+CD11c+ subset (Fig. 6b and Supplementary Fig. 6b, online). We noted higher numbers of cells producing more abundant IL-7 within the DC region of the spleen of Il7r-/- compared with Rag1-/- or wild-type mice (Fig. 6c). Thus, IL-7Rα signaling facilitates downregulation of MHCII expression and IL-7 production in DCs; these feedback loops could explain the detrimental effects of high systemic IL-7 quantities on CD4+ T cell homeostatic proliferation.

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