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Essential role of survivin, an inhibitor of apoptosis protein, in T cell development, maturation, and homeostasis.

Xing Z, Conway EM, Kang C, Winoto A - J. Exp. Med. (2003)

Bottom Line: Loss of survivin at a later stage resulted in normal thymic development, but peripheral T cells were immature and significantly reduced in number.In contrast to in vitro studies, loss of survivin does not lead to increased apoptosis.These data suggest that survivin is not essential for T cell apoptosis but is crucial for T cell maturation and proliferation, and survivin-mediated homeostatic expansion is an important physiological process of T cell development.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cell Biology, Division of Immunology and Cancer Research Laboratory, University of California at Berkeley, 469 LSA, Berkeley, CA 94720, USA.

ABSTRACT
Survivin is an inhibitor of apoptosis protein that also functions during mitosis. It is expressed in all common tumors and tissues with proliferating cells, including thymus. To examine its role in apoptosis and proliferation, we generated two T cell-specific survivin-deficient mouse lines with deletion occurring at different developmental stages. Analysis of early deleting survivin mice showed arrest at the pre-T cell receptor proliferating checkpoint. Loss of survivin at a later stage resulted in normal thymic development, but peripheral T cells were immature and significantly reduced in number. In contrast to in vitro studies, loss of survivin does not lead to increased apoptosis. However, newborn thymocyte homeostatic and mitogen-induced proliferation of survivin-deficient T cells were greatly impaired. These data suggest that survivin is not essential for T cell apoptosis but is crucial for T cell maturation and proliferation, and survivin-mediated homeostatic expansion is an important physiological process of T cell development.

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Reduced number of peripheral T cells in young mice and their elevated HSA level. (A) The absolute cell numbers of DP, SP (CD4+ CD8− or CD8+ CD4−), thymocytes, and peripheral T cells in newborn CD4-survivin mice and the littermate controls (n = 5). (B) Representative flow cytometric profile of splenocytes from 0–1-wk-old CD4-survivin mice. The experiments have been repeated at least three times with similar findings. (C) CD8 versus HSA flow cytometric profile of peripheral T cells from CD4-survivin and control littermates. (D) Impaired CD25 activation marker in CD4-survivin peripheral T cells. Splenic cells from CD4-survivin mice and their littermate controls (WT) were stimulated with anti-CD3/CD28 antibodies for 18 h and stained with anti-CD4 and anti-CD25 antibodies. The CD4+ gated cell profiles are shown here.
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fig4: Reduced number of peripheral T cells in young mice and their elevated HSA level. (A) The absolute cell numbers of DP, SP (CD4+ CD8− or CD8+ CD4−), thymocytes, and peripheral T cells in newborn CD4-survivin mice and the littermate controls (n = 5). (B) Representative flow cytometric profile of splenocytes from 0–1-wk-old CD4-survivin mice. The experiments have been repeated at least three times with similar findings. (C) CD8 versus HSA flow cytometric profile of peripheral T cells from CD4-survivin and control littermates. (D) Impaired CD25 activation marker in CD4-survivin peripheral T cells. Splenic cells from CD4-survivin mice and their littermate controls (WT) were stimulated with anti-CD3/CD28 antibodies for 18 h and stained with anti-CD4 and anti-CD25 antibodies. The CD4+ gated cell profiles are shown here.

Mentions: The apparent reduction of peripheral T cells in CD4-survivin mice might be due to increased apoptosis or lack of proliferation (see below). We reasoned that if apoptosis were involved, the number of peripheral T cells in younger survivin-deficient animals would be the same as in the wild-type controls. Once in the periphery, they would then gradually disappear. In cases where mature T cells were depleted of their TCR α gene, CD8+ cells die with a half-life of 16 d, whereas CD4+ cells die with a half-life of 46 d (50). Staining with annexin V did not show any increase in apoptosis of the T cells of newborn or adult survivin-deficient mice (see below). In contrast, flow cytometric analysis showed that the reduction of peripheral T cells in CD4-survivin mice was even more pronounced in newborn (0–1-wk-old) mice. Although the subpopulations and cell numbers of the newborn survivin-deficient thymocytes are identical to their littermate controls (Fig. 4 A), splenic and lymph node CD4+ CD8− and CD4− CD8+ T cells were reduced by up to 14-fold (Fig. 4, A and B; CD4-survivin mice: CD4 cells: 2.68 ± 0.55 × 105, CD8 cells: 0.94 ± 0.21 × 105; wild-type littermate controls: CD4 cells: 27.05 ± 1.71 × 105, CD8 cells: 13.20 ± 0.49 × 105). As proliferation of SP thymocytes is known to occur between 1 and 21 d after birth (3), these data suggest that survivin deficiency affects this proliferative step, leading to a reduced number of peripheral T cells.


Essential role of survivin, an inhibitor of apoptosis protein, in T cell development, maturation, and homeostasis.

Xing Z, Conway EM, Kang C, Winoto A - J. Exp. Med. (2003)

Reduced number of peripheral T cells in young mice and their elevated HSA level. (A) The absolute cell numbers of DP, SP (CD4+ CD8− or CD8+ CD4−), thymocytes, and peripheral T cells in newborn CD4-survivin mice and the littermate controls (n = 5). (B) Representative flow cytometric profile of splenocytes from 0–1-wk-old CD4-survivin mice. The experiments have been repeated at least three times with similar findings. (C) CD8 versus HSA flow cytometric profile of peripheral T cells from CD4-survivin and control littermates. (D) Impaired CD25 activation marker in CD4-survivin peripheral T cells. Splenic cells from CD4-survivin mice and their littermate controls (WT) were stimulated with anti-CD3/CD28 antibodies for 18 h and stained with anti-CD4 and anti-CD25 antibodies. The CD4+ gated cell profiles are shown here.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC1887718&req=5

fig4: Reduced number of peripheral T cells in young mice and their elevated HSA level. (A) The absolute cell numbers of DP, SP (CD4+ CD8− or CD8+ CD4−), thymocytes, and peripheral T cells in newborn CD4-survivin mice and the littermate controls (n = 5). (B) Representative flow cytometric profile of splenocytes from 0–1-wk-old CD4-survivin mice. The experiments have been repeated at least three times with similar findings. (C) CD8 versus HSA flow cytometric profile of peripheral T cells from CD4-survivin and control littermates. (D) Impaired CD25 activation marker in CD4-survivin peripheral T cells. Splenic cells from CD4-survivin mice and their littermate controls (WT) were stimulated with anti-CD3/CD28 antibodies for 18 h and stained with anti-CD4 and anti-CD25 antibodies. The CD4+ gated cell profiles are shown here.
Mentions: The apparent reduction of peripheral T cells in CD4-survivin mice might be due to increased apoptosis or lack of proliferation (see below). We reasoned that if apoptosis were involved, the number of peripheral T cells in younger survivin-deficient animals would be the same as in the wild-type controls. Once in the periphery, they would then gradually disappear. In cases where mature T cells were depleted of their TCR α gene, CD8+ cells die with a half-life of 16 d, whereas CD4+ cells die with a half-life of 46 d (50). Staining with annexin V did not show any increase in apoptosis of the T cells of newborn or adult survivin-deficient mice (see below). In contrast, flow cytometric analysis showed that the reduction of peripheral T cells in CD4-survivin mice was even more pronounced in newborn (0–1-wk-old) mice. Although the subpopulations and cell numbers of the newborn survivin-deficient thymocytes are identical to their littermate controls (Fig. 4 A), splenic and lymph node CD4+ CD8− and CD4− CD8+ T cells were reduced by up to 14-fold (Fig. 4, A and B; CD4-survivin mice: CD4 cells: 2.68 ± 0.55 × 105, CD8 cells: 0.94 ± 0.21 × 105; wild-type littermate controls: CD4 cells: 27.05 ± 1.71 × 105, CD8 cells: 13.20 ± 0.49 × 105). As proliferation of SP thymocytes is known to occur between 1 and 21 d after birth (3), these data suggest that survivin deficiency affects this proliferative step, leading to a reduced number of peripheral T cells.

Bottom Line: Loss of survivin at a later stage resulted in normal thymic development, but peripheral T cells were immature and significantly reduced in number.In contrast to in vitro studies, loss of survivin does not lead to increased apoptosis.These data suggest that survivin is not essential for T cell apoptosis but is crucial for T cell maturation and proliferation, and survivin-mediated homeostatic expansion is an important physiological process of T cell development.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cell Biology, Division of Immunology and Cancer Research Laboratory, University of California at Berkeley, 469 LSA, Berkeley, CA 94720, USA.

ABSTRACT
Survivin is an inhibitor of apoptosis protein that also functions during mitosis. It is expressed in all common tumors and tissues with proliferating cells, including thymus. To examine its role in apoptosis and proliferation, we generated two T cell-specific survivin-deficient mouse lines with deletion occurring at different developmental stages. Analysis of early deleting survivin mice showed arrest at the pre-T cell receptor proliferating checkpoint. Loss of survivin at a later stage resulted in normal thymic development, but peripheral T cells were immature and significantly reduced in number. In contrast to in vitro studies, loss of survivin does not lead to increased apoptosis. However, newborn thymocyte homeostatic and mitogen-induced proliferation of survivin-deficient T cells were greatly impaired. These data suggest that survivin is not essential for T cell apoptosis but is crucial for T cell maturation and proliferation, and survivin-mediated homeostatic expansion is an important physiological process of T cell development.

Show MeSH
Related in: MedlinePlus