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IL-7 and IL-15 independently program the differentiation of intestinal CD3-NKp46+ cell subsets from Id2-dependent precursors.

Satoh-Takayama N, Lesjean-Pottier S, Vieira P, Sawa S, Eberl G, Vosshenrich CA, Di Santo JP - J. Exp. Med. (2010)

Bottom Line: Overexpression of IL-15 in intestinal epithelial cells expanded NK1.1(+) cells within the gut but had no effect on absolute numbers of the CD127(+)NK1.1(-)Rorc(+) subset of CD3(-)NKp46(+) cells.In contrast, IL-7 deficiency strongly reduced the overall numbers of CD3(-)NKp46(+)NK1.1(-) cells that express Rorc and produce IL-22 but failed to restrict homeostasis of classical intestinal NK1.1(+) cells.These studies highlight the independent cytokine regulation of functionally diverse intestinal NKp46(+) cell subsets.

View Article: PubMed Central - HTML - PubMed

Affiliation: Cytokines and Lymphoid Development Unit, Institut Pasteur, 75724 Paris, France.

ABSTRACT
The natural cytotoxicity receptor NKp46 (encoded by Ncr1) was recently shown to identify a subset of noncytotoxic, Rag-independent gut lymphocytes that express the transcription factor Rorc, produce interleukin (IL)-22, and provide innate immune protection at the intestinal mucosa. Intestinal CD3(-)NKp46(+) cells are phenotypically heterogeneous, comprising a minority subset that resembles classical mature splenic natural killer (NK) cells (NK1.1(+), Ly49(+)) but also a large CD127(+)NK1.1(-) subset of lymphoid tissue inducer (LTi)-like Rorc(+) cells that has been proposed to include NK cell precursors. We investigated the developmental relationships between these intestinal CD3(-)NKp46(+) subsets. Gut CD3(-)NKp46(+) cells were related to LTi and NK cells in requiring the transcriptional inhibitor Id2 for normal development. Overexpression of IL-15 in intestinal epithelial cells expanded NK1.1(+) cells within the gut but had no effect on absolute numbers of the CD127(+)NK1.1(-)Rorc(+) subset of CD3(-)NKp46(+) cells. In contrast, IL-7 deficiency strongly reduced the overall numbers of CD3(-)NKp46(+)NK1.1(-) cells that express Rorc and produce IL-22 but failed to restrict homeostasis of classical intestinal NK1.1(+) cells. Finally, in vivo fate-mapping experiments demonstrated that intestinal NK1.1(+)CD127(-) cells are not the progeny of Rorc-expressing progenitors, indicating that CD127(+)NK1.1(-)Rorc(+) cells are not canonical NK cell precursors. These studies highlight the independent cytokine regulation of functionally diverse intestinal NKp46(+) cell subsets.

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Normal development of splenic and intestinal CD3−NKp46+ cell subsets requires Id2. (A) NK1.1 versus CD127 expression on gated CD3−NKp46+ splenocytes and small intestinal (SI) LPLs of WT and Id2−/− mice. Subset frequencies are indicated in one representative experiment out of six performed. (B) RORγt expression in intestinal CD3−NKp46+ subsets in WT (bold line) and Id2−/− mice (shaded histogram). The dotted line depicts staining of CD3−NKp46+ cells from Rorc−/− mice. (C) IL-23–induced IL-22 expression in intestinal CD3−NKp46+CD127+ cells from WT and Id2−/− mice. Results indicate frequencies from one out of two independent experiments.
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fig1: Normal development of splenic and intestinal CD3−NKp46+ cell subsets requires Id2. (A) NK1.1 versus CD127 expression on gated CD3−NKp46+ splenocytes and small intestinal (SI) LPLs of WT and Id2−/− mice. Subset frequencies are indicated in one representative experiment out of six performed. (B) RORγt expression in intestinal CD3−NKp46+ subsets in WT (bold line) and Id2−/− mice (shaded histogram). The dotted line depicts staining of CD3−NKp46+ cells from Rorc−/− mice. (C) IL-23–induced IL-22 expression in intestinal CD3−NKp46+CD127+ cells from WT and Id2−/− mice. Results indicate frequencies from one out of two independent experiments.

Mentions: To understand the developmental relationship between distinct intestinal CD3−NKp46+ subsets, we first assessed the role for the transcriptional inhibitor Id2 in the homeostasis of these cells. Previous studies have shown that Id2 plays a critical role in the development of NK1.1+ NK cells (Yokota et al., 1999), and is essential for the development of LTi cells that express the transcription factor Rorc and coordinate programmed lymphoid tissue genesis during fetal life and inducible lymphoid structures in adult mice (Eberl and Littman, 2004). By comparing lamina propria lymphocytes (LPLs) from WT and Id2-deficient (Id2−/−) mice, we found that normal development of all intestinal CD3−NKp46+ cell subsets required Id2. Percentages of intestinal CD3−NKp46+ cell subsets that differentially express CD127 and/or NK1.1 were severely reduced in the absence of Id2 (Fig. 1 A), resulting in dramatically reduced absolute numbers of these cells (WT mice, 1.5 ± 0.2 × 105 cells; Id2−/− mice, ∼103 cells). In contrast, intestinal T cell homeostasis in the lamina propria was minimally perturbed (Fig. S1), whereas Id2 deficiency markedly reduced the frequency of splenic CD3−NKp46+ cells (essentially NK1.1+ NK cells; Fig. 1 A), consistent with previous reports (Yokota et al., 1999; Kim et al., 2004; Boos et al., 2007).


IL-7 and IL-15 independently program the differentiation of intestinal CD3-NKp46+ cell subsets from Id2-dependent precursors.

Satoh-Takayama N, Lesjean-Pottier S, Vieira P, Sawa S, Eberl G, Vosshenrich CA, Di Santo JP - J. Exp. Med. (2010)

Normal development of splenic and intestinal CD3−NKp46+ cell subsets requires Id2. (A) NK1.1 versus CD127 expression on gated CD3−NKp46+ splenocytes and small intestinal (SI) LPLs of WT and Id2−/− mice. Subset frequencies are indicated in one representative experiment out of six performed. (B) RORγt expression in intestinal CD3−NKp46+ subsets in WT (bold line) and Id2−/− mice (shaded histogram). The dotted line depicts staining of CD3−NKp46+ cells from Rorc−/− mice. (C) IL-23–induced IL-22 expression in intestinal CD3−NKp46+CD127+ cells from WT and Id2−/− mice. Results indicate frequencies from one out of two independent experiments.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2822619&req=5

fig1: Normal development of splenic and intestinal CD3−NKp46+ cell subsets requires Id2. (A) NK1.1 versus CD127 expression on gated CD3−NKp46+ splenocytes and small intestinal (SI) LPLs of WT and Id2−/− mice. Subset frequencies are indicated in one representative experiment out of six performed. (B) RORγt expression in intestinal CD3−NKp46+ subsets in WT (bold line) and Id2−/− mice (shaded histogram). The dotted line depicts staining of CD3−NKp46+ cells from Rorc−/− mice. (C) IL-23–induced IL-22 expression in intestinal CD3−NKp46+CD127+ cells from WT and Id2−/− mice. Results indicate frequencies from one out of two independent experiments.
Mentions: To understand the developmental relationship between distinct intestinal CD3−NKp46+ subsets, we first assessed the role for the transcriptional inhibitor Id2 in the homeostasis of these cells. Previous studies have shown that Id2 plays a critical role in the development of NK1.1+ NK cells (Yokota et al., 1999), and is essential for the development of LTi cells that express the transcription factor Rorc and coordinate programmed lymphoid tissue genesis during fetal life and inducible lymphoid structures in adult mice (Eberl and Littman, 2004). By comparing lamina propria lymphocytes (LPLs) from WT and Id2-deficient (Id2−/−) mice, we found that normal development of all intestinal CD3−NKp46+ cell subsets required Id2. Percentages of intestinal CD3−NKp46+ cell subsets that differentially express CD127 and/or NK1.1 were severely reduced in the absence of Id2 (Fig. 1 A), resulting in dramatically reduced absolute numbers of these cells (WT mice, 1.5 ± 0.2 × 105 cells; Id2−/− mice, ∼103 cells). In contrast, intestinal T cell homeostasis in the lamina propria was minimally perturbed (Fig. S1), whereas Id2 deficiency markedly reduced the frequency of splenic CD3−NKp46+ cells (essentially NK1.1+ NK cells; Fig. 1 A), consistent with previous reports (Yokota et al., 1999; Kim et al., 2004; Boos et al., 2007).

Bottom Line: Overexpression of IL-15 in intestinal epithelial cells expanded NK1.1(+) cells within the gut but had no effect on absolute numbers of the CD127(+)NK1.1(-)Rorc(+) subset of CD3(-)NKp46(+) cells.In contrast, IL-7 deficiency strongly reduced the overall numbers of CD3(-)NKp46(+)NK1.1(-) cells that express Rorc and produce IL-22 but failed to restrict homeostasis of classical intestinal NK1.1(+) cells.These studies highlight the independent cytokine regulation of functionally diverse intestinal NKp46(+) cell subsets.

View Article: PubMed Central - HTML - PubMed

Affiliation: Cytokines and Lymphoid Development Unit, Institut Pasteur, 75724 Paris, France.

ABSTRACT
The natural cytotoxicity receptor NKp46 (encoded by Ncr1) was recently shown to identify a subset of noncytotoxic, Rag-independent gut lymphocytes that express the transcription factor Rorc, produce interleukin (IL)-22, and provide innate immune protection at the intestinal mucosa. Intestinal CD3(-)NKp46(+) cells are phenotypically heterogeneous, comprising a minority subset that resembles classical mature splenic natural killer (NK) cells (NK1.1(+), Ly49(+)) but also a large CD127(+)NK1.1(-) subset of lymphoid tissue inducer (LTi)-like Rorc(+) cells that has been proposed to include NK cell precursors. We investigated the developmental relationships between these intestinal CD3(-)NKp46(+) subsets. Gut CD3(-)NKp46(+) cells were related to LTi and NK cells in requiring the transcriptional inhibitor Id2 for normal development. Overexpression of IL-15 in intestinal epithelial cells expanded NK1.1(+) cells within the gut but had no effect on absolute numbers of the CD127(+)NK1.1(-)Rorc(+) subset of CD3(-)NKp46(+) cells. In contrast, IL-7 deficiency strongly reduced the overall numbers of CD3(-)NKp46(+)NK1.1(-) cells that express Rorc and produce IL-22 but failed to restrict homeostasis of classical intestinal NK1.1(+) cells. Finally, in vivo fate-mapping experiments demonstrated that intestinal NK1.1(+)CD127(-) cells are not the progeny of Rorc-expressing progenitors, indicating that CD127(+)NK1.1(-)Rorc(+) cells are not canonical NK cell precursors. These studies highlight the independent cytokine regulation of functionally diverse intestinal NKp46(+) cell subsets.

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