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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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Flow cytometric analysis of Thy-1, TCRαβ, and TCRγδ  expression on IEL from heterozygous (IL-2Rβ+/−) and homozygous (IL2Rβ−/−) IL-2Rβ–deficient mice. IEL isolated from IL-2Rβ+/− or IL2Rβ−/− mice were stained with anti–Thy-1 mAb, and anti-TCRαβ or  anti-TCRγδ mAb, and viable cells were analyzed by flow cytometry.  Numbers represent the percentage of total cells found in each quadrant.
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Figure 1: Flow cytometric analysis of Thy-1, TCRαβ, and TCRγδ expression on IEL from heterozygous (IL-2Rβ+/−) and homozygous (IL2Rβ−/−) IL-2Rβ–deficient mice. IEL isolated from IL-2Rβ+/− or IL2Rβ−/− mice were stained with anti–Thy-1 mAb, and anti-TCRαβ or anti-TCRγδ mAb, and viable cells were analyzed by flow cytometry. Numbers represent the percentage of total cells found in each quadrant.

Mentions: IEL have been found to express the intermediate affinity form of the IL-2R (IL-2Rβγ) (19), and examination of IL-2Rβ expression has shown that IEL with high and low levels of IL-2Rβ can be identified (20). To address the role of IL-2Rβ in IEL cell development, flow cytometric analyses of IEL obtained from IL-2Rβ−/− and IL-2Rβ+/− mice were performed. Despite an equivalent number of total IEL cells, a distinctly different population profile was observed in IL-2Rβ−/− mice compared with that in their IL-2R+/− or wild-type littermates. As shown in both Fig. 1 and Table 1, IEL from normal mice comprise heterogeneous populations of TCRαβ+ and TCRγδ+ cells. However, IEL from IL2Rβ–deficient mice showed a preponderance of TCRαβ+ cells and a dramatic reduction in TCRγδ+ cells. The normal ratio of αβ:γδ cells in IEL (shown here in IL-2Rβ+/− mice) is ∼2:1, but this ratio was dramatically increased to 9:1 in IL-2Rβ−/− mice. The number of Thy-1− IEL cells was also profoundly decreased in the absence of IL-2Rβ. In IL-2Rβ+/− mice used as controls, more than half of both TCRαβ+ and TCRγδ+ IEL were negative for Thy-1. However, Thy-1− cells represented <5% of both αβ+ and γδ+ IEL in IL-2Rβ–deficient mice. Immunohistological analysis revealed cells that stained positively with antiTCRαβ mAb, but not with anti-TCRγδ mAb (data not shown), confirming the reduced number of TCRγδ+ IEL observed using FACS® analysis. Similar results have been reported for other cytokine receptor mutants. In IL-7Rα knockout mice, γδ T cells (including γδ IEL) failed to develop, whereas αβ T cells (including αβ IEL) were present in slightly reduced numbers, and NK cells were normal (21, 22; H. Kiyono, personal communication). The determination of γδ expression in spleen or lymph node cells has proven to be problematic in IL-2Rβ–deficient mice because of the increased αβ T cell and granulocyte populations occurring in these mutants. Because αβ cells normally constitute only a small proportion of overall spleen and lymph node cells, at this time we cannot distinguish between a relative and real decrease in γδ cell numbers in the knockout mouse as a whole.


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)

Flow cytometric analysis of Thy-1, TCRαβ, and TCRγδ  expression on IEL from heterozygous (IL-2Rβ+/−) and homozygous (IL2Rβ−/−) IL-2Rβ–deficient mice. IEL isolated from IL-2Rβ+/− or IL2Rβ−/− mice were stained with anti–Thy-1 mAb, and anti-TCRαβ or  anti-TCRγδ mAb, and viable cells were analyzed by flow cytometry.  Numbers represent the percentage of total cells found in each quadrant.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2196040&req=5

Figure 1: Flow cytometric analysis of Thy-1, TCRαβ, and TCRγδ expression on IEL from heterozygous (IL-2Rβ+/−) and homozygous (IL2Rβ−/−) IL-2Rβ–deficient mice. IEL isolated from IL-2Rβ+/− or IL2Rβ−/− mice were stained with anti–Thy-1 mAb, and anti-TCRαβ or anti-TCRγδ mAb, and viable cells were analyzed by flow cytometry. Numbers represent the percentage of total cells found in each quadrant.
Mentions: IEL have been found to express the intermediate affinity form of the IL-2R (IL-2Rβγ) (19), and examination of IL-2Rβ expression has shown that IEL with high and low levels of IL-2Rβ can be identified (20). To address the role of IL-2Rβ in IEL cell development, flow cytometric analyses of IEL obtained from IL-2Rβ−/− and IL-2Rβ+/− mice were performed. Despite an equivalent number of total IEL cells, a distinctly different population profile was observed in IL-2Rβ−/− mice compared with that in their IL-2R+/− or wild-type littermates. As shown in both Fig. 1 and Table 1, IEL from normal mice comprise heterogeneous populations of TCRαβ+ and TCRγδ+ cells. However, IEL from IL2Rβ–deficient mice showed a preponderance of TCRαβ+ cells and a dramatic reduction in TCRγδ+ cells. The normal ratio of αβ:γδ cells in IEL (shown here in IL-2Rβ+/− mice) is ∼2:1, but this ratio was dramatically increased to 9:1 in IL-2Rβ−/− mice. The number of Thy-1− IEL cells was also profoundly decreased in the absence of IL-2Rβ. In IL-2Rβ+/− mice used as controls, more than half of both TCRαβ+ and TCRγδ+ IEL were negative for Thy-1. However, Thy-1− cells represented <5% of both αβ+ and γδ+ IEL in IL-2Rβ–deficient mice. Immunohistological analysis revealed cells that stained positively with antiTCRαβ mAb, but not with anti-TCRγδ mAb (data not shown), confirming the reduced number of TCRγδ+ IEL observed using FACS® analysis. Similar results have been reported for other cytokine receptor mutants. In IL-7Rα knockout mice, γδ T cells (including γδ IEL) failed to develop, whereas αβ T cells (including αβ IEL) were present in slightly reduced numbers, and NK cells were normal (21, 22; H. Kiyono, personal communication). The determination of γδ expression in spleen or lymph node cells has proven to be problematic in IL-2Rβ–deficient mice because of the increased αβ T cell and granulocyte populations occurring in these mutants. Because αβ cells normally constitute only a small proportion of overall spleen and lymph node cells, at this time we cannot distinguish between a relative and real decrease in γδ cell numbers in the knockout mouse as a whole.

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