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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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Both wild-type Jak3  transgenes reconstitute T cell,  but not B cell, development in  Jak3−/− mice. (A) The bone  marrow, thymus, and spleen cells  of Jak3+/−, Jak3−/−, Jak3−/−  (tgkd), and 35-d-old Jak3−/−  (tgthy+spl) and Jak3−/− (tgthy) mice  were stained with the indicated  antibodies and analyzed by flow  cytometry. Staining is shown on  a logarithmic scale of fluorescence intensity. Numbers in the  quadrants indicate subpopulation percentages. The dot plots  are representative of average  staining profiles, although some  Jak3−/− individuals had greatly  increased CD4+/CD8+ ratios in  the thymus and spleen. (B) The  total cellularity of bone marrow,  thymus, and spleen of mice analyzed in these experiments is indicated. For each organ, Jak3+/−,  lane 1; Jak3−/−, lane 2; Jak3−/−  (tgthy+spl), lane 3; Jak3−/− (tgthy),  lane 4; and Jak3−/− (tgkd), lane 5  are shown. Note the reconstitution of normal thymocyte cellularity by both wild-type, but not  the kinase-dead, Jak3 transgenes.  Data shown are representative of  greater than six independent experiments.
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Figure 2: Both wild-type Jak3 transgenes reconstitute T cell, but not B cell, development in Jak3−/− mice. (A) The bone marrow, thymus, and spleen cells of Jak3+/−, Jak3−/−, Jak3−/− (tgkd), and 35-d-old Jak3−/− (tgthy+spl) and Jak3−/− (tgthy) mice were stained with the indicated antibodies and analyzed by flow cytometry. Staining is shown on a logarithmic scale of fluorescence intensity. Numbers in the quadrants indicate subpopulation percentages. The dot plots are representative of average staining profiles, although some Jak3−/− individuals had greatly increased CD4+/CD8+ ratios in the thymus and spleen. (B) The total cellularity of bone marrow, thymus, and spleen of mice analyzed in these experiments is indicated. For each organ, Jak3+/−, lane 1; Jak3−/−, lane 2; Jak3−/− (tgthy+spl), lane 3; Jak3−/− (tgthy), lane 4; and Jak3−/− (tgkd), lane 5 are shown. Note the reconstitution of normal thymocyte cellularity by both wild-type, but not the kinase-dead, Jak3 transgenes. Data shown are representative of greater than six independent experiments.

Mentions: Jak3−/− (tgthy+spl), Jak3−/− (tgthy), and Jak3−/− (tgkd) mice were analyzed to determine the reconstitution of both the B and T cell lineages. Flow cytometry analysis of bone marrow cells indicated that no reconstitution of B cell development had occurred in any of these lines, as assessed by the lack of CD45R (B220)+ IgM+ cells (Fig. 2 A). Staining of bone marrow cells with antibodies to CD43 and CD45R (B220) also indicated that the block in B cell development observed in the Jak3−/− mice is not corrected with any of the Lck promoter–driven Jak3 transgenes (data not shown). Analysis of  B cells in the spleen demonstrated a reduced level of CD45R (B220)+ IgM+ cells in the Jak3−/− mice expressing either wild-type or kinase-dead Jak3 transgenes compared with the Jak3+/− control (Fig. 2 A).


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

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

Both wild-type Jak3  transgenes reconstitute T cell,  but not B cell, development in  Jak3−/− mice. (A) The bone  marrow, thymus, and spleen cells  of Jak3+/−, Jak3−/−, Jak3−/−  (tgkd), and 35-d-old Jak3−/−  (tgthy+spl) and Jak3−/− (tgthy) mice  were stained with the indicated  antibodies and analyzed by flow  cytometry. Staining is shown on  a logarithmic scale of fluorescence intensity. Numbers in the  quadrants indicate subpopulation percentages. The dot plots  are representative of average  staining profiles, although some  Jak3−/− individuals had greatly  increased CD4+/CD8+ ratios in  the thymus and spleen. (B) The  total cellularity of bone marrow,  thymus, and spleen of mice analyzed in these experiments is indicated. For each organ, Jak3+/−,  lane 1; Jak3−/−, lane 2; Jak3−/−  (tgthy+spl), lane 3; Jak3−/− (tgthy),  lane 4; and Jak3−/− (tgkd), lane 5  are shown. Note the reconstitution of normal thymocyte cellularity by both wild-type, but not  the kinase-dead, Jak3 transgenes.  Data shown are representative of  greater than six independent experiments.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2196115&req=5

Figure 2: Both wild-type Jak3 transgenes reconstitute T cell, but not B cell, development in Jak3−/− mice. (A) The bone marrow, thymus, and spleen cells of Jak3+/−, Jak3−/−, Jak3−/− (tgkd), and 35-d-old Jak3−/− (tgthy+spl) and Jak3−/− (tgthy) mice were stained with the indicated antibodies and analyzed by flow cytometry. Staining is shown on a logarithmic scale of fluorescence intensity. Numbers in the quadrants indicate subpopulation percentages. The dot plots are representative of average staining profiles, although some Jak3−/− individuals had greatly increased CD4+/CD8+ ratios in the thymus and spleen. (B) The total cellularity of bone marrow, thymus, and spleen of mice analyzed in these experiments is indicated. For each organ, Jak3+/−, lane 1; Jak3−/−, lane 2; Jak3−/− (tgthy+spl), lane 3; Jak3−/− (tgthy), lane 4; and Jak3−/− (tgkd), lane 5 are shown. Note the reconstitution of normal thymocyte cellularity by both wild-type, but not the kinase-dead, Jak3 transgenes. Data shown are representative of greater than six independent experiments.
Mentions: Jak3−/− (tgthy+spl), Jak3−/− (tgthy), and Jak3−/− (tgkd) mice were analyzed to determine the reconstitution of both the B and T cell lineages. Flow cytometry analysis of bone marrow cells indicated that no reconstitution of B cell development had occurred in any of these lines, as assessed by the lack of CD45R (B220)+ IgM+ cells (Fig. 2 A). Staining of bone marrow cells with antibodies to CD43 and CD45R (B220) also indicated that the block in B cell development observed in the Jak3−/− mice is not corrected with any of the Lck promoter–driven Jak3 transgenes (data not shown). Analysis of  B cells in the spleen demonstrated a reduced level of CD45R (B220)+ IgM+ cells in the Jak3−/− mice expressing either wild-type or kinase-dead Jak3 transgenes compared with the Jak3+/− control (Fig. 2 A).

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