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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 on BM-derived cells inhibits CD4+ T cell homeostatic proliferation during lymphopenia. (a) Marilyn T cells were transferred into the indicated BM chimeras. On day +7 after lymphocyte transfer, Marilyn T cells recovered from the spleen were enumerated. Data show mean±s.e. (n=6 mice/group), results representative of three independent experiments. *, P<0.001. (b) CFSE-labeled wild-type CD4+CD45.1+ cells were transferred into indicated BM chimeras. Seven days post-transfer CFSE dilution was assessed (n=6-8 mice/group), results representative of two independent experiments. (c) Wild-type CD4+CD45.1+ cells were transferred into indicated BM chimeras. Seven days post-transfer donor cells recovered from the spleen were enumerated. Data show mean±s.e. (n=3-6 mice/group). *, P<0.05 and **, P<0.0001). (d) Lethally irradiated Il7-/- mice received a mixture of the indicated BM. Five weeks later, BM chimeras received CFSE-labeled wild-type CD45.1+ T cells and, 7 days later, CFSE dilution was analyzed, (n=6-10 mice/group, results representative of three independent experiments).
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Figure 4: IL-7 signaling on BM-derived cells inhibits CD4+ T cell homeostatic proliferation during lymphopenia. (a) Marilyn T cells were transferred into the indicated BM chimeras. On day +7 after lymphocyte transfer, Marilyn T cells recovered from the spleen were enumerated. Data show mean±s.e. (n=6 mice/group), results representative of three independent experiments. *, P<0.001. (b) CFSE-labeled wild-type CD4+CD45.1+ cells were transferred into indicated BM chimeras. Seven days post-transfer CFSE dilution was assessed (n=6-8 mice/group), results representative of two independent experiments. (c) Wild-type CD4+CD45.1+ cells were transferred into indicated BM chimeras. Seven days post-transfer donor cells recovered from the spleen were enumerated. Data show mean±s.e. (n=3-6 mice/group). *, P<0.05 and **, P<0.0001). (d) Lethally irradiated Il7-/- mice received a mixture of the indicated BM. Five weeks later, BM chimeras received CFSE-labeled wild-type CD45.1+ T cells and, 7 days later, CFSE dilution was analyzed, (n=6-10 mice/group, results representative of three independent experiments).

Mentions: As hosts with elevated levels of IL-7 derived from stroma showed limited CD4+ T cell homeostatic proliferation (Fig. 3), we hypothesized that IL-7 signaling through IL-7Rα+ on hematopoietic cells could regulate CD4+ T cell homeostatic proliferation in vivo. To test this, we measured CD4+ T cell homeostatic proliferation in BM chimeras engineered such that BM-derived cells could not receive IL-7 signals (Il7r-/- BM into Rag1-/- recipients and Rag1-/- Il2rγ-/- BM into Rag1-/- recipients). Notably, Il7r-/- and Il2rγ-/- BM supported marked homeostatic proliferation of Marilyn (Fig. 4a) or polyclonal CD4+ T cells (Fig. 4b,c). Similarly, chimeras wherein downstream mediators of IL-7 signaling were lacking in BM-derived cells (Stat5a-/-Stat5b-/- BM into Rag1-/- recipients) also supported robust homeostatic proliferation of polyclonal CD4+ T cell populations (Fig. 4b,c). These results demonstrated that IL-7 signaling via IL-7Rα and STAT5 in BM-derived cells inhibits CD4+ T cell homeostatic proliferation. Notably, the robust CD4+ T cell homeostatic proliferation observed in the absence of γc signaling on APCs rules out the possibility that thymic stromal lymphopoietin (TSLP), mediates this inhibitory effect.


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 on BM-derived cells inhibits CD4+ T cell homeostatic proliferation during lymphopenia. (a) Marilyn T cells were transferred into the indicated BM chimeras. On day +7 after lymphocyte transfer, Marilyn T cells recovered from the spleen were enumerated. Data show mean±s.e. (n=6 mice/group), results representative of three independent experiments. *, P<0.001. (b) CFSE-labeled wild-type CD4+CD45.1+ cells were transferred into indicated BM chimeras. Seven days post-transfer CFSE dilution was assessed (n=6-8 mice/group), results representative of two independent experiments. (c) Wild-type CD4+CD45.1+ cells were transferred into indicated BM chimeras. Seven days post-transfer donor cells recovered from the spleen were enumerated. Data show mean±s.e. (n=3-6 mice/group). *, P<0.05 and **, P<0.0001). (d) Lethally irradiated Il7-/- mice received a mixture of the indicated BM. Five weeks later, BM chimeras received CFSE-labeled wild-type CD45.1+ T cells and, 7 days later, CFSE dilution was analyzed, (n=6-10 mice/group, results representative of three independent experiments).
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Related In: Results  -  Collection

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Figure 4: IL-7 signaling on BM-derived cells inhibits CD4+ T cell homeostatic proliferation during lymphopenia. (a) Marilyn T cells were transferred into the indicated BM chimeras. On day +7 after lymphocyte transfer, Marilyn T cells recovered from the spleen were enumerated. Data show mean±s.e. (n=6 mice/group), results representative of three independent experiments. *, P<0.001. (b) CFSE-labeled wild-type CD4+CD45.1+ cells were transferred into indicated BM chimeras. Seven days post-transfer CFSE dilution was assessed (n=6-8 mice/group), results representative of two independent experiments. (c) Wild-type CD4+CD45.1+ cells were transferred into indicated BM chimeras. Seven days post-transfer donor cells recovered from the spleen were enumerated. Data show mean±s.e. (n=3-6 mice/group). *, P<0.05 and **, P<0.0001). (d) Lethally irradiated Il7-/- mice received a mixture of the indicated BM. Five weeks later, BM chimeras received CFSE-labeled wild-type CD45.1+ T cells and, 7 days later, CFSE dilution was analyzed, (n=6-10 mice/group, results representative of three independent experiments).
Mentions: As hosts with elevated levels of IL-7 derived from stroma showed limited CD4+ T cell homeostatic proliferation (Fig. 3), we hypothesized that IL-7 signaling through IL-7Rα+ on hematopoietic cells could regulate CD4+ T cell homeostatic proliferation in vivo. To test this, we measured CD4+ T cell homeostatic proliferation in BM chimeras engineered such that BM-derived cells could not receive IL-7 signals (Il7r-/- BM into Rag1-/- recipients and Rag1-/- Il2rγ-/- BM into Rag1-/- recipients). Notably, Il7r-/- and Il2rγ-/- BM supported marked homeostatic proliferation of Marilyn (Fig. 4a) or polyclonal CD4+ T cells (Fig. 4b,c). Similarly, chimeras wherein downstream mediators of IL-7 signaling were lacking in BM-derived cells (Stat5a-/-Stat5b-/- BM into Rag1-/- recipients) also supported robust homeostatic proliferation of polyclonal CD4+ T cell populations (Fig. 4b,c). These results demonstrated that IL-7 signaling via IL-7Rα and STAT5 in BM-derived cells inhibits CD4+ T cell homeostatic proliferation. Notably, the robust CD4+ T cell homeostatic proliferation observed in the absence of γc signaling on APCs rules out the possibility that thymic stromal lymphopoietin (TSLP), mediates this inhibitory effect.

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