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Abnormal development of intestinal intraepithelial lymphocytes and peripheral natural killer cells in mice lacking the IL-2 receptor beta chain.

Suzuki H, Duncan GS, Takimoto H, Mak TW - J. Exp. Med. (1997)

Bottom Line: However, the importance of IL-2R beta-mediated signaling in the growth and development of these cells has yet to be clearly established.This selective decrease indicates that IEL can be classified into those whose development and/or differentiation is dependent on IL-2R beta function and those for which IL-2R beta-mediated signaling is not essential.The dependence of NK cells and certain subclasses of IEL cells on IL-2R beta expression points to an essential role for signaling through this receptor, presumably by IL-2 and/or IL-15, in the development of lymphocyte-subsets of extrathymic origin.

View Article: PubMed Central - PubMed

Affiliation: Amgen Institute, Toronto, Ontario, Canada.

ABSTRACT
The interleukin-2 receptor beta chain (IL-2R beta) is expressed on a variety of hematopoietic cell types, including natural killer (NK) cells and nonconventional T lymphocyte subsets such as intestinal intraepithelial lymphocytes (IEL). However, the importance of IL-2R beta-mediated signaling in the growth and development of these cells has yet to be clearly established. We have investigated IEL and NK cells in mice deficient for IL-2R beta and describe here striking defects in the development of these cells. IL-2R beta-/- mice exhibited an abnormal IEL cell population, characterized by a dramatic reduction in T cell receptor alpha beta CD8 alpha alpha and T cell receptor gamma delta lymphocytes. This selective decrease indicates that IEL can be classified into those whose development and/or differentiation is dependent on IL-2R beta function and those for which IL-2R beta-mediated signaling is not essential. NK cell development was also found to be disrupted in IL-2R beta-deficient mice, characterized by a reduction in NK1.1+CD3- cells in the peripheral circulation and an absence of NK cytotoxic activity in vitro. The dependence of NK cells and certain subclasses of IEL cells on IL-2R beta expression points to an essential role for signaling through this receptor, presumably by IL-2 and/or IL-15, in the development of lymphocyte-subsets of extrathymic origin.

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NK cell cytolytic activity and development in IL-2Rβ–deficient mice. Top panels show lysis of YAC-1 target cells by (A) spleen  MNC from poly(I):(C )–treated animals or (B) spleen MNC incubated in  vitro with IL-12. IL-2Rβ+/− MNC are represented by closed symbols;  IL-2Rβ−/− MNC are represented by open symbols. Data are shown as  mean ± SEM for (A) five IL-2Rβ+/− and five IL-2Rβ/- mice and for  (B) four IL-2Rβ+/− and two IL-2Rβ−/− mice, analyzed in two separate  experiments. (C) Flow cytometric analysis of NK1.1 and CD3 expression  on NK cells in IL-2Rβ–deficient mice. PB cells from IL-2Rβ+/− and IL2Rβ−/− mice were stained with anti-NK1.1 and anti-CD3, and 10,000  viable lymphocytes were gated. Numbers represent the percentage of  NK1.1+ cells in the gated population for a representative individual from  each group.
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Figure 3: NK cell cytolytic activity and development in IL-2Rβ–deficient mice. Top panels show lysis of YAC-1 target cells by (A) spleen MNC from poly(I):(C )–treated animals or (B) spleen MNC incubated in vitro with IL-12. IL-2Rβ+/− MNC are represented by closed symbols; IL-2Rβ−/− MNC are represented by open symbols. Data are shown as mean ± SEM for (A) five IL-2Rβ+/− and five IL-2Rβ/- mice and for (B) four IL-2Rβ+/− and two IL-2Rβ−/− mice, analyzed in two separate experiments. (C) Flow cytometric analysis of NK1.1 and CD3 expression on NK cells in IL-2Rβ–deficient mice. PB cells from IL-2Rβ+/− and IL2Rβ−/− mice were stained with anti-NK1.1 and anti-CD3, and 10,000 viable lymphocytes were gated. Numbers represent the percentage of NK1.1+ cells in the gated population for a representative individual from each group.

Mentions: NK cell–mediated cytotoxicity was evaluated using spleen MNC as a source of NK cells and the prototypic NK target cell line YAC-1. No cytotoxic activity was apparent in unstimulated spleen MNC of 3–5-wk-old wild-type or mutant mice (data not shown). To study in vivo induction of NK activity, mice were treated with the type I interferon inducer poly(I):poly(C). While substantial NK cell–mediated cytotoxic activity was induced in IL-2Rβ+/− mice, no cytotoxic activity was apparent in spleen NK cells derived from IL-2Rβ−/− mice (Fig. 3 A). To examine the activation of NK activity in vitro, spleen MNC from IL-2Rβ+/− and IL-2Rβ−/− mice were incubated overnight with IL-12. IL-12 induced significant cytolytic activity in MNC of IL2Rβ+/− mice but was completely ineffective in inducing detectable NK cytolytic activity in IL-2Rβ−/− MNC (Fig. 3 B). Analysis of IFN-γ production (by ELISA [Intertest γ; Genzyme, Cambridge, MA]) in culture supernatants of spleen MNC incubated with IL-12 revealed a 270-fold increase in IFN-γ production over unstimulated controls in IL-2Rβ+/− cells, but only a 2-fold increase in IL-2Rβ−/− cells (data not shown). These results strongly indicate an absence of functional NK cells in IL-2Rβ–deficient mice.


Abnormal development of intestinal intraepithelial lymphocytes and peripheral natural killer cells in mice lacking the IL-2 receptor beta chain.

Suzuki H, Duncan GS, Takimoto H, Mak TW - J. Exp. Med. (1997)

NK cell cytolytic activity and development in IL-2Rβ–deficient mice. Top panels show lysis of YAC-1 target cells by (A) spleen  MNC from poly(I):(C )–treated animals or (B) spleen MNC incubated in  vitro with IL-12. IL-2Rβ+/− MNC are represented by closed symbols;  IL-2Rβ−/− MNC are represented by open symbols. Data are shown as  mean ± SEM for (A) five IL-2Rβ+/− and five IL-2Rβ/- mice and for  (B) four IL-2Rβ+/− and two IL-2Rβ−/− mice, analyzed in two separate  experiments. (C) Flow cytometric analysis of NK1.1 and CD3 expression  on NK cells in IL-2Rβ–deficient mice. PB cells from IL-2Rβ+/− and IL2Rβ−/− mice were stained with anti-NK1.1 and anti-CD3, and 10,000  viable lymphocytes were gated. Numbers represent the percentage of  NK1.1+ cells in the gated population for a representative individual from  each group.
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Related In: Results  -  Collection

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Figure 3: NK cell cytolytic activity and development in IL-2Rβ–deficient mice. Top panels show lysis of YAC-1 target cells by (A) spleen MNC from poly(I):(C )–treated animals or (B) spleen MNC incubated in vitro with IL-12. IL-2Rβ+/− MNC are represented by closed symbols; IL-2Rβ−/− MNC are represented by open symbols. Data are shown as mean ± SEM for (A) five IL-2Rβ+/− and five IL-2Rβ/- mice and for (B) four IL-2Rβ+/− and two IL-2Rβ−/− mice, analyzed in two separate experiments. (C) Flow cytometric analysis of NK1.1 and CD3 expression on NK cells in IL-2Rβ–deficient mice. PB cells from IL-2Rβ+/− and IL2Rβ−/− mice were stained with anti-NK1.1 and anti-CD3, and 10,000 viable lymphocytes were gated. Numbers represent the percentage of NK1.1+ cells in the gated population for a representative individual from each group.
Mentions: NK cell–mediated cytotoxicity was evaluated using spleen MNC as a source of NK cells and the prototypic NK target cell line YAC-1. No cytotoxic activity was apparent in unstimulated spleen MNC of 3–5-wk-old wild-type or mutant mice (data not shown). To study in vivo induction of NK activity, mice were treated with the type I interferon inducer poly(I):poly(C). While substantial NK cell–mediated cytotoxic activity was induced in IL-2Rβ+/− mice, no cytotoxic activity was apparent in spleen NK cells derived from IL-2Rβ−/− mice (Fig. 3 A). To examine the activation of NK activity in vitro, spleen MNC from IL-2Rβ+/− and IL-2Rβ−/− mice were incubated overnight with IL-12. IL-12 induced significant cytolytic activity in MNC of IL2Rβ+/− mice but was completely ineffective in inducing detectable NK cytolytic activity in IL-2Rβ−/− MNC (Fig. 3 B). Analysis of IFN-γ production (by ELISA [Intertest γ; Genzyme, Cambridge, MA]) in culture supernatants of spleen MNC incubated with IL-12 revealed a 270-fold increase in IFN-γ production over unstimulated controls in IL-2Rβ+/− cells, but only a 2-fold increase in IL-2Rβ−/− cells (data not shown). These results strongly indicate an absence of functional NK cells in IL-2Rβ–deficient mice.

Bottom Line: However, the importance of IL-2R beta-mediated signaling in the growth and development of these cells has yet to be clearly established.This selective decrease indicates that IEL can be classified into those whose development and/or differentiation is dependent on IL-2R beta function and those for which IL-2R beta-mediated signaling is not essential.The dependence of NK cells and certain subclasses of IEL cells on IL-2R beta expression points to an essential role for signaling through this receptor, presumably by IL-2 and/or IL-15, in the development of lymphocyte-subsets of extrathymic origin.

View Article: PubMed Central - PubMed

Affiliation: Amgen Institute, Toronto, Ontario, Canada.

ABSTRACT
The interleukin-2 receptor beta chain (IL-2R beta) is expressed on a variety of hematopoietic cell types, including natural killer (NK) cells and nonconventional T lymphocyte subsets such as intestinal intraepithelial lymphocytes (IEL). However, the importance of IL-2R beta-mediated signaling in the growth and development of these cells has yet to be clearly established. We have investigated IEL and NK cells in mice deficient for IL-2R beta and describe here striking defects in the development of these cells. IL-2R beta-/- mice exhibited an abnormal IEL cell population, characterized by a dramatic reduction in T cell receptor alpha beta CD8 alpha alpha and T cell receptor gamma delta lymphocytes. This selective decrease indicates that IEL can be classified into those whose development and/or differentiation is dependent on IL-2R beta function and those for which IL-2R beta-mediated signaling is not essential. NK cell development was also found to be disrupted in IL-2R beta-deficient mice, characterized by a reduction in NK1.1+CD3- cells in the peripheral circulation and an absence of NK cytotoxic activity in vitro. The dependence of NK cells and certain subclasses of IEL cells on IL-2R beta expression points to an essential role for signaling through this receptor, presumably by IL-2 and/or IL-15, in the development of lymphocyte-subsets of extrathymic origin.

Show MeSH
Related in: MedlinePlus