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The common cytokine receptor gamma chain plays an essential role in regulating lymphoid homeostasis.

Nakajima H, Shores EW, Noguchi M, Leonard WJ - J. Exp. Med. (1997)

Bottom Line: Although the manner in which these diverse events are coordinated is incompletely understood, cytokines are known to play major roles.Whereas IL-7 is essential for lymphoid development, IL-2 and IL-4 are vital for lymphocyte proliferation.However, because the CD4+ T cells accumulate, it is clear that the rate of proliferation exceeds the rate of cell death.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, Bethesda, Maryland 20892, USA.

ABSTRACT
In the immune system, there is a careful regulation not only of lymphoid development and proliferation, but also of the fate of activated and proliferating cells. Although the manner in which these diverse events are coordinated is incompletely understood, cytokines are known to play major roles. Whereas IL-7 is essential for lymphoid development, IL-2 and IL-4 are vital for lymphocyte proliferation. The receptors for each of these cytokines contain the common cytokine receptor gamma chain (gammac), and it was previously shown that gammac-deficient mice exhibit severely compromised development and responsiveness to IL-2, IL-4, and IL-7. Nevertheless, these mice exhibit an age-dependent accumulation of splenic CD4+ T cells, the majority of which have a phenotype typical of memory/activated cells. When gammac-deficient mice were mated to DO11.10 T cell receptor (TCR) transgenic mice, only the T cells bearing endogenous TCRs had this phenotype, suggesting that its acquisition was TCR dependent. Not only do the CD4+ T cells from gammac-deficient mice exhibit an activated phenotype and greatly enhanced incorporation of bromodeoxyuridine but, consistent with the lack of gammac-dependent survival signals, they also exhibit an augmented rate of apoptosis. However, because the CD4+ T cells accumulate, it is clear that the rate of proliferation exceeds the rate of cell death. Thus, surprisingly, although gammac-independent signals are sufficient to mediate expansion of CD4+ T cells in these mice, gammac-dependent signals are required to regulate the fate of activated CD4+ T cells, underscoring the importance of gammac-dependent signals in controlling lymphoid homeo-stasis.

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Activated CD4+ T cells accumulate in an age-dependent  fashion in γc-deficient mice and exhibit increased BrdU uptake. (A) The  number of splenic CD4+ T cells in γc-deficient (closed diamonds) and wildtype (open squares) mice was calculated as the product of the number of  splenocytes and the percent of CD4+ T cells, based on staining with antiCD4 Cy-Chrome and analysis on a FACSort® (Becton Dickinson) using  Lysis II software. Shown are mean ± SEM (n = 4–9 at each timepoint).  (B) Size of CD4+ T cells. Splenocytes from 6-wk-old mice were stained  with anti-CD4 Cy-Chrome and PI, and cell size of viable cells was assessed by forward light scatter (FSC); data are shown on a linear scale. (C)  Activation markers expressed on CD4+ T cells. Splenocytes were stained  with anti-CD4 Cy-Chrome and either PE conjugated anti-CD62L (L-selectin), anti-CD69, or anti-CD25. Data were gated on CD4+ cells and displayed on a log scale. The data shown are representative of six experiments. (D) BrdU uptake of thymocytes and splenic CD4+ T cells. Mice  were injected twice with BrdU (see Material and Methods). 16 h after the  second injection, purified splenic CD4+ T cells and thymocytes were  stained with anti-BrdU FITC according to the Becton Dickinson protocol and analyzed on a FACSort®. Histograms show BrdU staining (log  scale); the numbers above the gate represent the mean percentage of  BrdU-positive cells from four experiments. When mice were injected  with PBS instead of BrdU, less than 0.1% of thymocytes and splenic  CD4+ T cells were stained with anti-BrdU FITC (data not shown).
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Figure 1: Activated CD4+ T cells accumulate in an age-dependent fashion in γc-deficient mice and exhibit increased BrdU uptake. (A) The number of splenic CD4+ T cells in γc-deficient (closed diamonds) and wildtype (open squares) mice was calculated as the product of the number of splenocytes and the percent of CD4+ T cells, based on staining with antiCD4 Cy-Chrome and analysis on a FACSort® (Becton Dickinson) using Lysis II software. Shown are mean ± SEM (n = 4–9 at each timepoint). (B) Size of CD4+ T cells. Splenocytes from 6-wk-old mice were stained with anti-CD4 Cy-Chrome and PI, and cell size of viable cells was assessed by forward light scatter (FSC); data are shown on a linear scale. (C) Activation markers expressed on CD4+ T cells. Splenocytes were stained with anti-CD4 Cy-Chrome and either PE conjugated anti-CD62L (L-selectin), anti-CD69, or anti-CD25. Data were gated on CD4+ cells and displayed on a log scale. The data shown are representative of six experiments. (D) BrdU uptake of thymocytes and splenic CD4+ T cells. Mice were injected twice with BrdU (see Material and Methods). 16 h after the second injection, purified splenic CD4+ T cells and thymocytes were stained with anti-BrdU FITC according to the Becton Dickinson protocol and analyzed on a FACSort®. Histograms show BrdU staining (log scale); the numbers above the gate represent the mean percentage of BrdU-positive cells from four experiments. When mice were injected with PBS instead of BrdU, less than 0.1% of thymocytes and splenic CD4+ T cells were stained with anti-BrdU FITC (data not shown).

Mentions: Assuming that cells that have taken up BrdU at 20 h have divided once, the apparent replication rate/day, r, can be calculated from the equation: percent BrdU uptake/20 h × 24 h/d = 2r/(100 + r). Based on the data in Fig. 1 D, this yields values for r of 21.43%/d for γc-deficient mice and 6.32%/d for wild-type mice. Assuming that no death occurs and that there is no new migration of cells from thymus to periphery (neither assumption is likely to be correct), we can estimate the number of cells that might exist after 63 d of growth (from 3–12 wk of age) as 1.3 × 106 × (1.2143)63 = 2.66 × 1011 CD4+ splenic T cells instead of 5.28 × 107 cells for γc-deficient mice and 9.1 × 106 × (1.0632)63 = 4.31 × 108 cells instead of 1.67 × 107 for wild-type mice. Although not accurate, these calculations suggest that survival rates for the cells differ between the wild-type and γc-deficient mice. Again, assuming no new migration from the thymus to periphery and a constant replication rate, the survival rate/day can be estimated as ∼87% for γc-deficient mice and 95% for wild-type mice, suggesting that cells from the γc-deficient mice had an increased rate of cell death (see below).


The common cytokine receptor gamma chain plays an essential role in regulating lymphoid homeostasis.

Nakajima H, Shores EW, Noguchi M, Leonard WJ - J. Exp. Med. (1997)

Activated CD4+ T cells accumulate in an age-dependent  fashion in γc-deficient mice and exhibit increased BrdU uptake. (A) The  number of splenic CD4+ T cells in γc-deficient (closed diamonds) and wildtype (open squares) mice was calculated as the product of the number of  splenocytes and the percent of CD4+ T cells, based on staining with antiCD4 Cy-Chrome and analysis on a FACSort® (Becton Dickinson) using  Lysis II software. Shown are mean ± SEM (n = 4–9 at each timepoint).  (B) Size of CD4+ T cells. Splenocytes from 6-wk-old mice were stained  with anti-CD4 Cy-Chrome and PI, and cell size of viable cells was assessed by forward light scatter (FSC); data are shown on a linear scale. (C)  Activation markers expressed on CD4+ T cells. Splenocytes were stained  with anti-CD4 Cy-Chrome and either PE conjugated anti-CD62L (L-selectin), anti-CD69, or anti-CD25. Data were gated on CD4+ cells and displayed on a log scale. The data shown are representative of six experiments. (D) BrdU uptake of thymocytes and splenic CD4+ T cells. Mice  were injected twice with BrdU (see Material and Methods). 16 h after the  second injection, purified splenic CD4+ T cells and thymocytes were  stained with anti-BrdU FITC according to the Becton Dickinson protocol and analyzed on a FACSort®. Histograms show BrdU staining (log  scale); the numbers above the gate represent the mean percentage of  BrdU-positive cells from four experiments. When mice were injected  with PBS instead of BrdU, less than 0.1% of thymocytes and splenic  CD4+ T cells were stained with anti-BrdU FITC (data not shown).
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Related In: Results  -  Collection

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Figure 1: Activated CD4+ T cells accumulate in an age-dependent fashion in γc-deficient mice and exhibit increased BrdU uptake. (A) The number of splenic CD4+ T cells in γc-deficient (closed diamonds) and wildtype (open squares) mice was calculated as the product of the number of splenocytes and the percent of CD4+ T cells, based on staining with antiCD4 Cy-Chrome and analysis on a FACSort® (Becton Dickinson) using Lysis II software. Shown are mean ± SEM (n = 4–9 at each timepoint). (B) Size of CD4+ T cells. Splenocytes from 6-wk-old mice were stained with anti-CD4 Cy-Chrome and PI, and cell size of viable cells was assessed by forward light scatter (FSC); data are shown on a linear scale. (C) Activation markers expressed on CD4+ T cells. Splenocytes were stained with anti-CD4 Cy-Chrome and either PE conjugated anti-CD62L (L-selectin), anti-CD69, or anti-CD25. Data were gated on CD4+ cells and displayed on a log scale. The data shown are representative of six experiments. (D) BrdU uptake of thymocytes and splenic CD4+ T cells. Mice were injected twice with BrdU (see Material and Methods). 16 h after the second injection, purified splenic CD4+ T cells and thymocytes were stained with anti-BrdU FITC according to the Becton Dickinson protocol and analyzed on a FACSort®. Histograms show BrdU staining (log scale); the numbers above the gate represent the mean percentage of BrdU-positive cells from four experiments. When mice were injected with PBS instead of BrdU, less than 0.1% of thymocytes and splenic CD4+ T cells were stained with anti-BrdU FITC (data not shown).
Mentions: Assuming that cells that have taken up BrdU at 20 h have divided once, the apparent replication rate/day, r, can be calculated from the equation: percent BrdU uptake/20 h × 24 h/d = 2r/(100 + r). Based on the data in Fig. 1 D, this yields values for r of 21.43%/d for γc-deficient mice and 6.32%/d for wild-type mice. Assuming that no death occurs and that there is no new migration of cells from thymus to periphery (neither assumption is likely to be correct), we can estimate the number of cells that might exist after 63 d of growth (from 3–12 wk of age) as 1.3 × 106 × (1.2143)63 = 2.66 × 1011 CD4+ splenic T cells instead of 5.28 × 107 cells for γc-deficient mice and 9.1 × 106 × (1.0632)63 = 4.31 × 108 cells instead of 1.67 × 107 for wild-type mice. Although not accurate, these calculations suggest that survival rates for the cells differ between the wild-type and γc-deficient mice. Again, assuming no new migration from the thymus to periphery and a constant replication rate, the survival rate/day can be estimated as ∼87% for γc-deficient mice and 95% for wild-type mice, suggesting that cells from the γc-deficient mice had an increased rate of cell death (see below).

Bottom Line: Although the manner in which these diverse events are coordinated is incompletely understood, cytokines are known to play major roles.Whereas IL-7 is essential for lymphoid development, IL-2 and IL-4 are vital for lymphocyte proliferation.However, because the CD4+ T cells accumulate, it is clear that the rate of proliferation exceeds the rate of cell death.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, Bethesda, Maryland 20892, USA.

ABSTRACT
In the immune system, there is a careful regulation not only of lymphoid development and proliferation, but also of the fate of activated and proliferating cells. Although the manner in which these diverse events are coordinated is incompletely understood, cytokines are known to play major roles. Whereas IL-7 is essential for lymphoid development, IL-2 and IL-4 are vital for lymphocyte proliferation. The receptors for each of these cytokines contain the common cytokine receptor gamma chain (gammac), and it was previously shown that gammac-deficient mice exhibit severely compromised development and responsiveness to IL-2, IL-4, and IL-7. Nevertheless, these mice exhibit an age-dependent accumulation of splenic CD4+ T cells, the majority of which have a phenotype typical of memory/activated cells. When gammac-deficient mice were mated to DO11.10 T cell receptor (TCR) transgenic mice, only the T cells bearing endogenous TCRs had this phenotype, suggesting that its acquisition was TCR dependent. Not only do the CD4+ T cells from gammac-deficient mice exhibit an activated phenotype and greatly enhanced incorporation of bromodeoxyuridine but, consistent with the lack of gammac-dependent survival signals, they also exhibit an augmented rate of apoptosis. However, because the CD4+ T cells accumulate, it is clear that the rate of proliferation exceeds the rate of cell death. Thus, surprisingly, although gammac-independent signals are sufficient to mediate expansion of CD4+ T cells in these mice, gammac-dependent signals are required to regulate the fate of activated CD4+ T cells, underscoring the importance of gammac-dependent signals in controlling lymphoid homeo-stasis.

Show MeSH
Related in: MedlinePlus