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Peripheral expression of Jak3 is required to maintain T lymphocyte function.

Thomis DC, Berg LJ - J. Exp. Med. (1997)

Bottom Line: The Jak family tyrosine kinase, Jak3, is involved in signaling through cytokine receptors that utilize the common gamma chain (gammac), such as those for IL-2, IL-4, IL-7, IL-9, and IL-15.Jak3 expression in the thymus restores normal T cell development, including CD8+, gammadelta, and natural killer cells.However, the loss of Jak3 protein in peripheral T cells leads to the Jak3-/- phenotype, demonstrating that Jak3 is constitutively required to maintain T cell function.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, USA.

ABSTRACT
The Jak family tyrosine kinase, Jak3, is involved in signaling through cytokine receptors that utilize the common gamma chain (gammac), such as those for IL-2, IL-4, IL-7, IL-9, and IL-15. Recent studies of Jak3-deficient mice and humans have demonstrated that Jak3 plays a critical role in B and T lymphocyte maturation and function. The T lymphocyte defects in Jak3-deficient mice include a small thymus, a decrease in peripheral CD8+ cells, an increase in the surface expression of activation markers, and a severe reduction in proliferative and cytokine secretion responses to mitogenic stimuli. To determine whether the peripheral T lymphocyte defects result from aberrant maturation in the thymus or from the absence of Jak3 protein in peripheral T cells, we generated reconstituted mice that express normal levels of Jak3 protein in the thymus but lose Jak3 expression in peripheral T cells. Jak3 expression in the thymus restores normal T cell development, including CD8+, gammadelta, and natural killer cells. However, the loss of Jak3 protein in peripheral T cells leads to the Jak3-/- phenotype, demonstrating that Jak3 is constitutively required to maintain T cell function.

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Splenic CD4+ T  cells from Jak3−/− (tgthy) mice  acquire increasing numbers of  phenotypically activated T cells  as the mice age. Splenocytes  from Jak3+/−, Jak3−/−, Jak3−/−  (tgthy+spl), Jak3−/− (tgkd), and  three Jak3−/− (tgthy) mice of different ages were stained with antibodies to CD4, CD8, and  CD44 or CD62L (MEL-14).  The staining of CD44 (top) and  CD62L (bottom) on gated  CD4+ T cells is shown on a logarithmic scale of fluorescence intensity. All histograms are directly comparable except the  staining of the 25-d-old Jak3−/−  (tgthy) mouse, which was performed with a different lot of  streptavidin-FITC, resulting in a  brighter overall level of CD44  and CD62L fluorescence. Data  shown are representative of  greater than six independent experiments.
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Figure 3: Splenic CD4+ T cells from Jak3−/− (tgthy) mice acquire increasing numbers of phenotypically activated T cells as the mice age. Splenocytes from Jak3+/−, Jak3−/−, Jak3−/− (tgthy+spl), Jak3−/− (tgkd), and three Jak3−/− (tgthy) mice of different ages were stained with antibodies to CD4, CD8, and CD44 or CD62L (MEL-14). The staining of CD44 (top) and CD62L (bottom) on gated CD4+ T cells is shown on a logarithmic scale of fluorescence intensity. All histograms are directly comparable except the staining of the 25-d-old Jak3−/− (tgthy) mouse, which was performed with a different lot of streptavidin-FITC, resulting in a brighter overall level of CD44 and CD62L fluorescence. Data shown are representative of greater than six independent experiments.

Mentions: The reconstituted Jak3−/− mice were examined for the surface phenotype and function of their T cells. Splenic T cells were stained with antibodies to CD4, CD8, and a panel of activation markers. Analysis of CD44 and CD62L (MEL-14) levels on gated CD4+ T cells indicate that Jak3−/− T cells resemble activated or memory T cells, expressing high levels of CD44 and low levels of CD62L (Fig. 3). The T cells in the Jak3−/− (tgthy+spl) mice are completely restored to normal, appearing indistinguishable from control (Jak3+/−) T cells at all ages analyzed (Fig. 3; data not shown). In contrast, the splenic CD4+ T cells from the Jak3−/− (tgkd) mice are indistinguishable from Jak3−/− T cells (Fig. 3). Most interestingly, CD4+ T cells from Jak3−/− (tgthy) mice have a cell surface phenotype that appears to correlate with peripheral Jak3 protein expression (Fig. 3). In the youngest Jak3−/− (tgthy) mouse shown (25 d of age), where Jak3 protein is still detectable in the spleen (see Fig. 1 B), the majority of CD4+ T cells are CD44lo and CD62Lhi. In an older mouse (35 d of age), where Jak3 protein is no longer detectable in the spleen (see Fig. 1 C), two populations of  T cells can be seen. In an even older mouse (42 d of age), most of the T cells in the Jak3−/− (tgthy) mouse are CD44hi and CD62Llo, and resemble the Jak3−/− T cells. This gradual appearance of phenotypically aberrant peripheral T cells, which correlates with the age of the mice, indicates that Jak3 protein is constitutively required to maintain a normal population of resting T cells. In total, nine Jak3−/− (tgthy) mice and eleven Jak3−/− (tgthy+spl) mice have been analyzed; in all cases, the peripheral T cells from the Jak3−/− (tgthy+spl) mice resembled wild-type T cells, whereas the peripheral T cells from the Jak3−/− (tgthy) mice had a surface phenotype that roughly correlated with the age of the mice. However, some variation in the precise age at which the vast majority of Jak3−/− (tgthy) peripheral T cells acquired the Jak3−/− surface phenotype was observed, most likely owing to variations in the loss of Jak3 protein from these cells. Overall, a comparable pattern of activation marker expression is observed on splenic CD8+ T cells in all mice analyzed (data not shown).


Peripheral expression of Jak3 is required to maintain T lymphocyte function.

Thomis DC, Berg LJ - J. Exp. Med. (1997)

Splenic CD4+ T  cells from Jak3−/− (tgthy) mice  acquire increasing numbers of  phenotypically activated T cells  as the mice age. Splenocytes  from Jak3+/−, Jak3−/−, Jak3−/−  (tgthy+spl), Jak3−/− (tgkd), and  three Jak3−/− (tgthy) mice of different ages were stained with antibodies to CD4, CD8, and  CD44 or CD62L (MEL-14).  The staining of CD44 (top) and  CD62L (bottom) on gated  CD4+ T cells is shown on a logarithmic scale of fluorescence intensity. All histograms are directly comparable except the  staining of the 25-d-old Jak3−/−  (tgthy) mouse, which was performed with a different lot of  streptavidin-FITC, resulting in a  brighter overall level of CD44  and CD62L fluorescence. Data  shown are representative of  greater than six independent experiments.
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Related In: Results  -  Collection

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Figure 3: Splenic CD4+ T cells from Jak3−/− (tgthy) mice acquire increasing numbers of phenotypically activated T cells as the mice age. Splenocytes from Jak3+/−, Jak3−/−, Jak3−/− (tgthy+spl), Jak3−/− (tgkd), and three Jak3−/− (tgthy) mice of different ages were stained with antibodies to CD4, CD8, and CD44 or CD62L (MEL-14). The staining of CD44 (top) and CD62L (bottom) on gated CD4+ T cells is shown on a logarithmic scale of fluorescence intensity. All histograms are directly comparable except the staining of the 25-d-old Jak3−/− (tgthy) mouse, which was performed with a different lot of streptavidin-FITC, resulting in a brighter overall level of CD44 and CD62L fluorescence. Data shown are representative of greater than six independent experiments.
Mentions: The reconstituted Jak3−/− mice were examined for the surface phenotype and function of their T cells. Splenic T cells were stained with antibodies to CD4, CD8, and a panel of activation markers. Analysis of CD44 and CD62L (MEL-14) levels on gated CD4+ T cells indicate that Jak3−/− T cells resemble activated or memory T cells, expressing high levels of CD44 and low levels of CD62L (Fig. 3). The T cells in the Jak3−/− (tgthy+spl) mice are completely restored to normal, appearing indistinguishable from control (Jak3+/−) T cells at all ages analyzed (Fig. 3; data not shown). In contrast, the splenic CD4+ T cells from the Jak3−/− (tgkd) mice are indistinguishable from Jak3−/− T cells (Fig. 3). Most interestingly, CD4+ T cells from Jak3−/− (tgthy) mice have a cell surface phenotype that appears to correlate with peripheral Jak3 protein expression (Fig. 3). In the youngest Jak3−/− (tgthy) mouse shown (25 d of age), where Jak3 protein is still detectable in the spleen (see Fig. 1 B), the majority of CD4+ T cells are CD44lo and CD62Lhi. In an older mouse (35 d of age), where Jak3 protein is no longer detectable in the spleen (see Fig. 1 C), two populations of  T cells can be seen. In an even older mouse (42 d of age), most of the T cells in the Jak3−/− (tgthy) mouse are CD44hi and CD62Llo, and resemble the Jak3−/− T cells. This gradual appearance of phenotypically aberrant peripheral T cells, which correlates with the age of the mice, indicates that Jak3 protein is constitutively required to maintain a normal population of resting T cells. In total, nine Jak3−/− (tgthy) mice and eleven Jak3−/− (tgthy+spl) mice have been analyzed; in all cases, the peripheral T cells from the Jak3−/− (tgthy+spl) mice resembled wild-type T cells, whereas the peripheral T cells from the Jak3−/− (tgthy) mice had a surface phenotype that roughly correlated with the age of the mice. However, some variation in the precise age at which the vast majority of Jak3−/− (tgthy) peripheral T cells acquired the Jak3−/− surface phenotype was observed, most likely owing to variations in the loss of Jak3 protein from these cells. Overall, a comparable pattern of activation marker expression is observed on splenic CD8+ T cells in all mice analyzed (data not shown).

Bottom Line: The Jak family tyrosine kinase, Jak3, is involved in signaling through cytokine receptors that utilize the common gamma chain (gammac), such as those for IL-2, IL-4, IL-7, IL-9, and IL-15.Jak3 expression in the thymus restores normal T cell development, including CD8+, gammadelta, and natural killer cells.However, the loss of Jak3 protein in peripheral T cells leads to the Jak3-/- phenotype, demonstrating that Jak3 is constitutively required to maintain T cell function.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, USA.

ABSTRACT
The Jak family tyrosine kinase, Jak3, is involved in signaling through cytokine receptors that utilize the common gamma chain (gammac), such as those for IL-2, IL-4, IL-7, IL-9, and IL-15. Recent studies of Jak3-deficient mice and humans have demonstrated that Jak3 plays a critical role in B and T lymphocyte maturation and function. The T lymphocyte defects in Jak3-deficient mice include a small thymus, a decrease in peripheral CD8+ cells, an increase in the surface expression of activation markers, and a severe reduction in proliferative and cytokine secretion responses to mitogenic stimuli. To determine whether the peripheral T lymphocyte defects result from aberrant maturation in the thymus or from the absence of Jak3 protein in peripheral T cells, we generated reconstituted mice that express normal levels of Jak3 protein in the thymus but lose Jak3 expression in peripheral T cells. Jak3 expression in the thymus restores normal T cell development, including CD8+, gammadelta, and natural killer cells. However, the loss of Jak3 protein in peripheral T cells leads to the Jak3-/- phenotype, demonstrating that Jak3 is constitutively required to maintain T cell function.

Show MeSH
Related in: MedlinePlus