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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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Activation of splenic  CD4+ T cells in γc-deficient mice  is TCR dependent. γc-deficient  mice were back-crossed to  BALB/c mice (H-2d/d, Jackson  Laboratory) for three generations. Since the γc gene is located  on the X chromosome, DO10  TCR transgenic male mice (H-2d/d)  were mated with BALB/c γc+/−  heterozygous female mice (H-2d/d).  These matings yielded four  genotypes (assessed by PCR of  tail DNA) of male mice  (DO10−γc+/Y, DO10+γc+/Y,  DO10−γc−/Y, and DO10+γc−/Y)  (A). In (A), also shown are the  total number and CD4/CD8  staining of splenocytes from  5-wk-old mice. As previously  reported (32), DO10+ male  mice expressing wild-type γc  (DO10+γc+/Y mice) exhibit an  increased CD4/CD8 ratio as  compared with DO10−γc+/Y mice  (first two panels), but consistent  with the increased CD4/CD8  ratios previously observed in  γc-deficient mice (6, 7),  DO10+γc−/Y mice exhibited an  even greater CD4/CD8 ratio  (fourth panel). Results are representative of three separate experiments. (B) Histograms of KJ1-26  mAb (anti-idiotype TCR) staining (gated on CD4+ T cells). (C)  Splenocytes were stained by  three color flow cytometric analysis for expression of KJ1-26,  CD62L, and CD4. Data were  gated on KJ1-26− CD4+ (endogenous TCR) (top histogram)  or KJ1-26+CD4+ (transgenic  TCR) (bottom histogram) T cells.  The histograms show profiles  for CD62L expression (log  scale); the percent of CD62Lhigh  cells is indicated.
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Figure 3: Activation of splenic CD4+ T cells in γc-deficient mice is TCR dependent. γc-deficient mice were back-crossed to BALB/c mice (H-2d/d, Jackson Laboratory) for three generations. Since the γc gene is located on the X chromosome, DO10 TCR transgenic male mice (H-2d/d) were mated with BALB/c γc+/− heterozygous female mice (H-2d/d). These matings yielded four genotypes (assessed by PCR of tail DNA) of male mice (DO10−γc+/Y, DO10+γc+/Y, DO10−γc−/Y, and DO10+γc−/Y) (A). In (A), also shown are the total number and CD4/CD8 staining of splenocytes from 5-wk-old mice. As previously reported (32), DO10+ male mice expressing wild-type γc (DO10+γc+/Y mice) exhibit an increased CD4/CD8 ratio as compared with DO10−γc+/Y mice (first two panels), but consistent with the increased CD4/CD8 ratios previously observed in γc-deficient mice (6, 7), DO10+γc−/Y mice exhibited an even greater CD4/CD8 ratio (fourth panel). Results are representative of three separate experiments. (B) Histograms of KJ1-26 mAb (anti-idiotype TCR) staining (gated on CD4+ T cells). (C) Splenocytes were stained by three color flow cytometric analysis for expression of KJ1-26, CD62L, and CD4. Data were gated on KJ1-26− CD4+ (endogenous TCR) (top histogram) or KJ1-26+CD4+ (transgenic TCR) (bottom histogram) T cells. The histograms show profiles for CD62L expression (log scale); the percent of CD62Lhigh cells is indicated.

Mentions: There are at least two possible explanations for why peripheral CD4+ T cells in γc-deficient mice were already activated without exogenous stimulation. In the first model, the activated phenotype does not require TCR stimulation (TCR-independent activation model); instead, γc-dependent signals are required for keeping mature CD4+ T cells in a naive stage and, that without such signals, these cells are activated nonspecifically. In the second model, peripheral CD4+ T cells in γc-deficient mice respond to self- or environmental antigens (TCR-dependent activation model). We investigated these possibilities using mice expressing MHC class II–restricted transgenic TCRs specific for ovalbumin (DO10 mice) or cytochrome c (AND mice). In these experiments, the mice were not exposed to the specific antigens. In DO10 male mice deficient in γc (DO10+γc−/Y mice), far fewer splenocytes were found than in DO10−γc−/Y mice (6.4 × 106 versus 79 × 106 cells/spleen) (Fig. 3 A). Analogous differences were also seen between AND+γc−/Y and AND−γc−/Y mice (2.7 × 106 versus 50 × 106 cells/ spleen). These data suggested that endogenous TCR expression might be important in regulating CD4+ T cell accumulation. Using the DO10+γc−/Y mice, we compared the relative frequency of memory (CD62Llow) and naive (CD62Lhigh) phenotypes in splenic CD4+ T cells expressing transgenic (KJ1-26+) versus endogenous (KJ1-26−) TCRs. Approximately 70% of CD4+ T cells from DO10+γc−/Y mice express the transgenic TCR (Fig. 3 B, fourth histogram), analogous to DO10+γc+/Y mice (second histogram). Surprisingly, although relatively high numbers of KJ126+CD4+ T cells in DO10+γc−/Y mice were CD62Lhigh (naive phenotype), similar to the finding for DO10+γc+/Y mice (84.9% versus 84.6%) (Fig. 3 C, bottom), relatively few of the endogenous KJ1-26− CD4+ T cells in DO10+γc−/Y mice were CD62Lhigh (10%), similar to the finding for DO10−γc−/Y mice (8.3%) (Fig. 3 C, top). Thus, the CD62Llow phenotype correlated with the presence of endogenous TCRs. Analogous results were found in AND TCR transgenic γc-deficient (AND+γc−/Y) mice. In AND+γc−/Y mice, 93% of transgenic TCR+ (Vα11+) CD4+ T cells were CD62Lhigh, similar to AND+γc+/Y mice (94%). These results support the TCR-dependent activation model and suggested that TCR(s) expressed on expanding peripheral CD4+ T cells in γc-deficient mice are specific for self-antigen or environmental antigens. The finding that over 80% of adult γc-deficient mice (C57BL/6 background) develop an inflammatory bowel disease (data not shown) is consistent with the possibility of self-reactive CD4+ T cells in these mice.


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)

Activation of splenic  CD4+ T cells in γc-deficient mice  is TCR dependent. γc-deficient  mice were back-crossed to  BALB/c mice (H-2d/d, Jackson  Laboratory) for three generations. Since the γc gene is located  on the X chromosome, DO10  TCR transgenic male mice (H-2d/d)  were mated with BALB/c γc+/−  heterozygous female mice (H-2d/d).  These matings yielded four  genotypes (assessed by PCR of  tail DNA) of male mice  (DO10−γc+/Y, DO10+γc+/Y,  DO10−γc−/Y, and DO10+γc−/Y)  (A). In (A), also shown are the  total number and CD4/CD8  staining of splenocytes from  5-wk-old mice. As previously  reported (32), DO10+ male  mice expressing wild-type γc  (DO10+γc+/Y mice) exhibit an  increased CD4/CD8 ratio as  compared with DO10−γc+/Y mice  (first two panels), but consistent  with the increased CD4/CD8  ratios previously observed in  γc-deficient mice (6, 7),  DO10+γc−/Y mice exhibited an  even greater CD4/CD8 ratio  (fourth panel). Results are representative of three separate experiments. (B) Histograms of KJ1-26  mAb (anti-idiotype TCR) staining (gated on CD4+ T cells). (C)  Splenocytes were stained by  three color flow cytometric analysis for expression of KJ1-26,  CD62L, and CD4. Data were  gated on KJ1-26− CD4+ (endogenous TCR) (top histogram)  or KJ1-26+CD4+ (transgenic  TCR) (bottom histogram) T cells.  The histograms show profiles  for CD62L expression (log  scale); the percent of CD62Lhigh  cells is indicated.
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Figure 3: Activation of splenic CD4+ T cells in γc-deficient mice is TCR dependent. γc-deficient mice were back-crossed to BALB/c mice (H-2d/d, Jackson Laboratory) for three generations. Since the γc gene is located on the X chromosome, DO10 TCR transgenic male mice (H-2d/d) were mated with BALB/c γc+/− heterozygous female mice (H-2d/d). These matings yielded four genotypes (assessed by PCR of tail DNA) of male mice (DO10−γc+/Y, DO10+γc+/Y, DO10−γc−/Y, and DO10+γc−/Y) (A). In (A), also shown are the total number and CD4/CD8 staining of splenocytes from 5-wk-old mice. As previously reported (32), DO10+ male mice expressing wild-type γc (DO10+γc+/Y mice) exhibit an increased CD4/CD8 ratio as compared with DO10−γc+/Y mice (first two panels), but consistent with the increased CD4/CD8 ratios previously observed in γc-deficient mice (6, 7), DO10+γc−/Y mice exhibited an even greater CD4/CD8 ratio (fourth panel). Results are representative of three separate experiments. (B) Histograms of KJ1-26 mAb (anti-idiotype TCR) staining (gated on CD4+ T cells). (C) Splenocytes were stained by three color flow cytometric analysis for expression of KJ1-26, CD62L, and CD4. Data were gated on KJ1-26− CD4+ (endogenous TCR) (top histogram) or KJ1-26+CD4+ (transgenic TCR) (bottom histogram) T cells. The histograms show profiles for CD62L expression (log scale); the percent of CD62Lhigh cells is indicated.
Mentions: There are at least two possible explanations for why peripheral CD4+ T cells in γc-deficient mice were already activated without exogenous stimulation. In the first model, the activated phenotype does not require TCR stimulation (TCR-independent activation model); instead, γc-dependent signals are required for keeping mature CD4+ T cells in a naive stage and, that without such signals, these cells are activated nonspecifically. In the second model, peripheral CD4+ T cells in γc-deficient mice respond to self- or environmental antigens (TCR-dependent activation model). We investigated these possibilities using mice expressing MHC class II–restricted transgenic TCRs specific for ovalbumin (DO10 mice) or cytochrome c (AND mice). In these experiments, the mice were not exposed to the specific antigens. In DO10 male mice deficient in γc (DO10+γc−/Y mice), far fewer splenocytes were found than in DO10−γc−/Y mice (6.4 × 106 versus 79 × 106 cells/spleen) (Fig. 3 A). Analogous differences were also seen between AND+γc−/Y and AND−γc−/Y mice (2.7 × 106 versus 50 × 106 cells/ spleen). These data suggested that endogenous TCR expression might be important in regulating CD4+ T cell accumulation. Using the DO10+γc−/Y mice, we compared the relative frequency of memory (CD62Llow) and naive (CD62Lhigh) phenotypes in splenic CD4+ T cells expressing transgenic (KJ1-26+) versus endogenous (KJ1-26−) TCRs. Approximately 70% of CD4+ T cells from DO10+γc−/Y mice express the transgenic TCR (Fig. 3 B, fourth histogram), analogous to DO10+γc+/Y mice (second histogram). Surprisingly, although relatively high numbers of KJ126+CD4+ T cells in DO10+γc−/Y mice were CD62Lhigh (naive phenotype), similar to the finding for DO10+γc+/Y mice (84.9% versus 84.6%) (Fig. 3 C, bottom), relatively few of the endogenous KJ1-26− CD4+ T cells in DO10+γc−/Y mice were CD62Lhigh (10%), similar to the finding for DO10−γc−/Y mice (8.3%) (Fig. 3 C, top). Thus, the CD62Llow phenotype correlated with the presence of endogenous TCRs. Analogous results were found in AND TCR transgenic γc-deficient (AND+γc−/Y) mice. In AND+γc−/Y mice, 93% of transgenic TCR+ (Vα11+) CD4+ T cells were CD62Lhigh, similar to AND+γc+/Y mice (94%). These results support the TCR-dependent activation model and suggested that TCR(s) expressed on expanding peripheral CD4+ T cells in γc-deficient mice are specific for self-antigen or environmental antigens. The finding that over 80% of adult γc-deficient mice (C57BL/6 background) develop an inflammatory bowel disease (data not shown) is consistent with the possibility of self-reactive CD4+ T cells in these mice.

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