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T cell development and activation in Jak3-deficient mice
A M Baird1, D C Thomis, L J Berg
1Department of Pathology, University of Massachusetts Medical Center, Worcester 01655, USA.
Abstract:
Jak3, a member of the Janus family of tyrosine kinases, participates in signaling through cytokine receptors that contain the common gamma-chain, including the receptors for interleukin (IL)-2, IL-4, IL-7, IL-9, and IL-15. Jak3- and gamma c-deficient mice have pleiotropic defects that can be attributed to their inability to respond to multiple specific cytokines. A great deal of recent work has focused on the T cell defects in these mutant mice. Specifically, Jak3- and gamma c-deficient mice have small thymuses revealing a defect in T cell development, and in addition, have functionally unresponsive peripheral T cells with an activated/memory cell phenotype. The thymic defect in these mutant mice strongly resembles that seen in IL-7 and IL-7 receptor knockout mice, suggesting that the lack of IL-7 receptor signaling accounts for this defect in Jak3-/- and gamma c- mice. To characterize this defect further, we have examined the earliest stages of T cell development in adult and fetal Jak3-/- thymuses. These studies identify two discrete developmental defects at the CD4-CD8- stage of T cell maturation. Analyses of peripheral T cells in Jak3-/- and gamma c- mice have also revealed a number of abnormalities. All of the T cells in these mutant mice have an activated phenotype and a large fraction of them are proliferating in vivo. In addition, Jak3-/- and gamma c- T cells are more prone to undergo apoptosis than wild-type T cells. Together, these features account for the decreased IL-2 secretion by in vitro-stimulated Jak3-/- T cells. Overall, many of the lymphoid defects of Jak3- and gamma c-deficient mice can be accounted for by the lack of IL-7R and IL-2R signaling; however, other cytokine systems must also be involved in maintaining peripheral T cell homeostasis.
Insights
Janus kinase 3 (Jak3) deficiency impairs T cell development and function by disrupting signaling pathways for key cytokines like IL-7 and IL-2. This leads to developmental defects and abnormal peripheral T cell responses.
Area of Science:
- Immunology
- Molecular Biology
- Cell Biology
Background:
- Janus kinase 3 (Jak3) is crucial for signaling pathways involving common gamma-chain cytokine receptors, including IL-2, IL-4, IL-7, IL-9, and IL-15.
- Deficiencies in Jak3 or the common gamma chain (gamma c) result in significant immune system defects, particularly affecting T cell development and function.
Purpose of the Study:
- To investigate the specific T cell developmental defects in Jak3- and gamma c-deficient mice.
- To elucidate the roles of IL-7 receptor and IL-2 receptor signaling in T cell maturation and peripheral T cell homeostasis.
Main Methods:
- Analysis of T cell development in the thymus of Jak3-deficient mice at both fetal and adult stages.
- Characterization of peripheral T cell phenotypes, proliferation, and apoptosis in Jak3- and gamma c-deficient mice.
Main Results:
- Two distinct developmental defects were identified at the CD4-CD8- stage of T cell maturation in Jak3-deficient thymuses.
- Peripheral T cells in Jak3- and gamma c-deficient mice exhibit an activated phenotype, in vivo proliferation, and increased susceptibility to apoptosis.
- These abnormalities correlate with decreased IL-2 secretion by stimulated T cells.
Conclusions:
- The lymphoid defects in Jak3- and gamma c-deficient mice are largely attributable to impaired IL-7R and IL-2R signaling.
- Other cytokine systems are also implicated in maintaining peripheral T cell homeostasis.