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Defective lymphoid development in mice lacking expression of the common cytokine receptor gamma chain
1Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892.
Abstract:
The common gamma chain (gamma c) of the IL-2, IL-4, IL-7, IL-9, and IL-15 receptors is defective in humans with XSCID. Mice lacking gamma c expression had hypoplastic thymuses; the thymocytes responded to gamma c-independent mitogens, but not gamma c-dependent stimuli. Splenic T cells were diminished at 3 weeks of age, but CD4+ T cells markedly increased by 4 weeks. B cells were greatly diminished in contrast with the situation in XSCID. NK cells, gamma delta intestinal intraepithelial lymphocytes, dendritic epidermal T cells, peripheral lymph nodes, and gut-associated lymphoid tissue were absent. These findings underscore the importance of gamma c in lymphoid development. Moreover, differences in humans and mice lacking gamma c expression indicate species-specific differences in the roles of gamma c-dependent cytokines or in the existence of redundant pathways. These mice provide an important model for studying the pathophysiology provide an important model for studying the pathophysiology of and gene therapy for human XSCID.
Insights
Mice lacking the common gamma chain (gamma c) showed impaired lymphoid development, highlighting its crucial role in immune cell function and providing a model for XSCID research.
Area of Science:
- Immunology
- Developmental Biology
- Genetics
Background:
- The common gamma chain (gamma c) is essential for multiple interleukin receptors, including IL-2, IL-4, IL-7, IL-9, and IL-15.
- Defects in gamma c are implicated in human X-linked Severe Combined Immunodeficiency (XSCID).
Purpose of the Study:
- To investigate the role of gamma c in lymphoid development using a mouse model.
- To compare the effects of gamma c deficiency in mice with human XSCID.
Main Methods:
- Generation and analysis of mice lacking gamma c expression.
- Assessment of thymocyte and splenic lymphocyte populations (T cells, B cells, NK cells).
- Evaluation of lymphoid tissues and immune cell subsets.
Main Results:
- Mice exhibited hypoplastic thymuses and impaired thymocyte responses to gamma c-dependent stimuli.
- Significant reductions in B cells and NK cells were observed, contrasting with human XSCID.
- Absence of gamma delta T cells, dendritic epidermal T cells, and certain lymphoid tissues was noted.
Conclusions:
- Gamma c is critical for the development of multiple lymphoid lineages.
- Species-specific differences in gamma c function or compensatory pathways exist between mice and humans.
- These mice serve as a valuable model for studying XSCID pathophysiology and gene therapy.