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Crucial role of Jak3 in negative selection of self-reactive T cells.

Saijo K, Park SY, Ishida Y, Arase H, Saito T - J. Exp. Med. (1997)

Bottom Line: In spite of the severely reduced number of lymphocytes in Jak3-deficient mice, the differentiation profile of thymocytes was normal and mature T cells accumulated in the periphery with age.All peripheral T cells were in the activation state and thus were unable to be activated further, as demonstrated by the failure of eliciting Ca2+ response upon T cell receptor (TCR) stimulation.These findings demonstrate a crucial function of Jak3 in the negative selection of autoreactive T cells and the maintenance of functional peripheral T cells.

View Article: PubMed Central - PubMed

Affiliation: Center for Biomedical Science, Chiba University School of Medicine, Inohana, Chuo-ku, Japan.

ABSTRACT
Jak3 mediates growth signals through cytokine receptors such as interleukin-2 (IL-2), IL-4, and IL-7, and its deficiency results in autosomal recessive SCID in mice and humans. In spite of the severely reduced number of lymphocytes in Jak3-deficient mice, the differentiation profile of thymocytes was normal and mature T cells accumulated in the periphery with age. However, we found that self-reactive T cells were not deleted in the thymus and the peripheral tissues in Jak3-deficient mice. All peripheral T cells were in the activation state and thus were unable to be activated further, as demonstrated by the failure of eliciting Ca2+ response upon T cell receptor (TCR) stimulation. From the analysis of TCR-transgenic Jak3-deficient mice, only self-reactive T cells appeared to be in the activated state and anergic. These findings demonstrate a crucial function of Jak3 in the negative selection of autoreactive T cells and the maintenance of functional peripheral T cells.

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Intracellular Ca2+ mobilization of thymocytes (A) and splenic  T cells (B) from Jak3-deficient mice (−/−) and wild-type littermates (+/+).  Thymocytes and splenocytes were stained with anti-CD4 and anti-CD8  mAbs, loaded with Indo-1, stimulated with cross-linking with 2C11 or  A23187 (Iono.), and then Ca2+ responses were measured. Data for CD4+  cells were represented. In both A and B, the peak (thick line) and sustained  line (dotted line) Ca2+ responses were shown.
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Figure 4: Intracellular Ca2+ mobilization of thymocytes (A) and splenic T cells (B) from Jak3-deficient mice (−/−) and wild-type littermates (+/+). Thymocytes and splenocytes were stained with anti-CD4 and anti-CD8 mAbs, loaded with Indo-1, stimulated with cross-linking with 2C11 or A23187 (Iono.), and then Ca2+ responses were measured. Data for CD4+ cells were represented. In both A and B, the peak (thick line) and sustained line (dotted line) Ca2+ responses were shown.

Mentions: To investigate the defects in TCR activation, we analyzed intracellular Ca2+ mobilization as an indicator of the early signal transduction pathway upon TCR stimulation. As shown in Fig. 4 A, thymocytes from Jak3−/− mice elicited almost comparable Ca2+ response to that of thymocytes from wild-type mice upon stimulation with both anti-CD3ε mAb cross-linking and Ca2+ ionophore. In contrast, splenic T cells from Jak3−/− mice failed to elicit Ca2+ response upon TCR cross-linking in spite of the fact that these cells showed Ca2+ flux upon stimulation with Ca2+ ionophore (Fig. 4 B). These data clearly demonstrate that splenic T cells from Jak3−/− mice have defects in early Ca2+ signaling upon activation through the TCR complex.


Crucial role of Jak3 in negative selection of self-reactive T cells.

Saijo K, Park SY, Ishida Y, Arase H, Saito T - J. Exp. Med. (1997)

Intracellular Ca2+ mobilization of thymocytes (A) and splenic  T cells (B) from Jak3-deficient mice (−/−) and wild-type littermates (+/+).  Thymocytes and splenocytes were stained with anti-CD4 and anti-CD8  mAbs, loaded with Indo-1, stimulated with cross-linking with 2C11 or  A23187 (Iono.), and then Ca2+ responses were measured. Data for CD4+  cells were represented. In both A and B, the peak (thick line) and sustained  line (dotted line) Ca2+ responses were shown.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2196119&req=5

Figure 4: Intracellular Ca2+ mobilization of thymocytes (A) and splenic T cells (B) from Jak3-deficient mice (−/−) and wild-type littermates (+/+). Thymocytes and splenocytes were stained with anti-CD4 and anti-CD8 mAbs, loaded with Indo-1, stimulated with cross-linking with 2C11 or A23187 (Iono.), and then Ca2+ responses were measured. Data for CD4+ cells were represented. In both A and B, the peak (thick line) and sustained line (dotted line) Ca2+ responses were shown.
Mentions: To investigate the defects in TCR activation, we analyzed intracellular Ca2+ mobilization as an indicator of the early signal transduction pathway upon TCR stimulation. As shown in Fig. 4 A, thymocytes from Jak3−/− mice elicited almost comparable Ca2+ response to that of thymocytes from wild-type mice upon stimulation with both anti-CD3ε mAb cross-linking and Ca2+ ionophore. In contrast, splenic T cells from Jak3−/− mice failed to elicit Ca2+ response upon TCR cross-linking in spite of the fact that these cells showed Ca2+ flux upon stimulation with Ca2+ ionophore (Fig. 4 B). These data clearly demonstrate that splenic T cells from Jak3−/− mice have defects in early Ca2+ signaling upon activation through the TCR complex.

Bottom Line: In spite of the severely reduced number of lymphocytes in Jak3-deficient mice, the differentiation profile of thymocytes was normal and mature T cells accumulated in the periphery with age.All peripheral T cells were in the activation state and thus were unable to be activated further, as demonstrated by the failure of eliciting Ca2+ response upon T cell receptor (TCR) stimulation.These findings demonstrate a crucial function of Jak3 in the negative selection of autoreactive T cells and the maintenance of functional peripheral T cells.

View Article: PubMed Central - PubMed

Affiliation: Center for Biomedical Science, Chiba University School of Medicine, Inohana, Chuo-ku, Japan.

ABSTRACT
Jak3 mediates growth signals through cytokine receptors such as interleukin-2 (IL-2), IL-4, and IL-7, and its deficiency results in autosomal recessive SCID in mice and humans. In spite of the severely reduced number of lymphocytes in Jak3-deficient mice, the differentiation profile of thymocytes was normal and mature T cells accumulated in the periphery with age. However, we found that self-reactive T cells were not deleted in the thymus and the peripheral tissues in Jak3-deficient mice. All peripheral T cells were in the activation state and thus were unable to be activated further, as demonstrated by the failure of eliciting Ca2+ response upon T cell receptor (TCR) stimulation. From the analysis of TCR-transgenic Jak3-deficient mice, only self-reactive T cells appeared to be in the activated state and anergic. These findings demonstrate a crucial function of Jak3 in the negative selection of autoreactive T cells and the maintenance of functional peripheral T cells.

Show MeSH
Related in: MedlinePlus