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Developmental defects of lymphoid cells in Jak3 kinase-deficient mice
S Y Park1, K Saijo, T Takahashi
1Division of Molecular Genetics, Chiba University School of Medicine, Japan.
Abstract:
Jak3 is a tyrosine kinase mediating cytokine receptor signaling through the association with the common gamma chain of the cytokine receptors such as IL-2, IL-4, IL-7, IL-9, and IL-15. Unlike other members of the Jak family, the expression of Jak3 is highly restricted in hematopoietic cells. To elucidate in vivo function of Jak3, Jak3-deficient mice were generated by homologous recombination. Mice homozygous for Jak3 null mutation showed severe defects, specifically in lymphoid cells. B cell precursors in bone marrow, thymocytes, and both T and B cells in the spleen drastically decreased, although these defects were significantly recovered as aging occurred. Peripheral lymph nodes, NK cells, dendritic epidermal T cells, and intestinal intraepithelial gamma delta T cells were absent. Normal number of hematopoietic stem cells in bone marrow from Jak3-deficient mice and the similar capability to generate myeloid and erythroid colonies as wild-type mice indicated specific defects in lymphoid stem cells. Furthermore, the abnormal architecture of lymphoid organs suggested the involvement of Jak3 in the function of epithelial cells. T cells developed in the mutant mice did not respond to either IL-2, IL-4, or IL-7. These findings establish the crucial role of Jak3 in the development of lymphoid cells.
Insights
Janus kinase 3 (Jak3) is essential for lymphoid cell development. Jak3 deficiency in mice leads to severe defects in immune cell populations and lymphoid organ structure, highlighting its critical role.
Area of Science:
- Immunology
- Molecular Biology
- Hematopoiesis
Background:
- Janus kinase 3 (Jak3) is a tyrosine kinase involved in cytokine receptor signaling via the common gamma chain.
- Jak3 expression is predominantly restricted to hematopoietic cells, suggesting a specialized role in immune cell development.
Purpose of the Study:
- To investigate the in vivo function of Jak3 in the development and function of immune cells.
- To elucidate the specific roles of Jak3 in lymphoid cell differentiation and organogenesis.
Main Methods:
- Generation of Jak3-deficient mice using homologous recombination.
- Analysis of immune cell populations, lymphoid organ architecture, and hematopoietic stem cell function in mutant mice.
- Assessment of T cell responsiveness to key cytokines (IL-2, IL-4, IL-7).
Main Results:
- Jak3 null mutation caused severe reductions in B cell precursors, thymocytes, and splenic T and B cells, with partial recovery during aging.
- Absence of peripheral lymph nodes, NK cells, dendritic epidermal T cells, and intestinal intraepithelial gamma delta T cells was observed.
- Developed T cells from Jak3-deficient mice showed impaired responses to IL-2, IL-4, and IL-7, indicating a critical signaling defect.
Conclusions:
- Jak3 plays a crucial and indispensable role in the development of lymphoid cells.
- The findings underscore the importance of Jak3 in establishing functional immune cell populations and lymphoid organ integrity.