Inactivation of c-Cbl reverses neonatal lethality and T cell developmental arrest of SLP-76-deficient mice
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Updated: Aug 23, 2026
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Published on: April 26, 2024
Y Jeffrey Chiang1, Connie L Sommers, Martha S Jordan
1Experimental Immunology Branch, Building 10, Room 4B36, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. chiangj@mail.nih.gov
Abstract:
c-Cbl is an adaptor protein that negatively regulates signal transduction events involved in thymic-positive selection. To further characterize the function of c-Cbl in T cell development, we analyzed the effect of c-Cbl inactivation in mice deficient in the scaffolding molecule SLP-76. SLP-76-deficient mice show a high frequency of neonatal lethality; and in surviving mice, T cell development is blocked at the DN3 stage. Inactivation of c-cbl completely reversed the neonatal lethality seen in SLP-76-deficient mice and partially reversed the T cell development arrest in these mice. SLP-76(-/-) Cbl(-/-) mice exhibited marked expansion of polarized T helper type (Th)1 and Th2 cell peripheral CD4(+) T cells, lymphoid infiltrates of parenchymal organs, and premature death. This rescue of T cell development is T cell receptor dependent because it does not occur in recombination activating gene 2(-/-) SLP-76(-/-) Cbl(-/-) triple knockout mice. Analysis of the signal transduction properties of SLP-76(-/-) Cbl(-/-) T cells reveals a novel SLP-76- and linker for activation of T cells-independent pathway of extracellular signal-regulated kinase activation, which is normally down-regulated by c-Cbl.
Insights
Inactivating c-Cbl protein in mice lacking SLP-76 rescued neonatal lethality and partially restored T cell development. This revealed a new signaling pathway crucial for T cell regulation.
Area of Science:
- Immunology
- Molecular Biology
- Cell Signaling
Background:
- c-Cbl is an adaptor protein that negatively regulates T cell signaling during thymic selection.
- SLP-76 is a scaffolding molecule essential for T cell development, with its deficiency causing neonatal lethality and developmental arrest.
- Understanding c-Cbl's role in T cell development requires examining its function in the context of SLP-76 deficiency.
Purpose of the Study:
- To investigate the functional role of c-Cbl in T cell development.
- To analyze the impact of c-Cbl inactivation on mice lacking SLP-76.
- To elucidate novel signaling pathways regulated by c-Cbl in T cells.
Main Methods:
- Generation of SLP-76-deficient and c-Cbl-deficient mice.
- Analysis of T cell development and survival in knockout mouse models.
- Investigation of T cell signaling pathways, including extracellular signal-regulated kinase (ERK) activation.
Main Results:
- Inactivation of c-Cbl completely rescued neonatal lethality in SLP-76-deficient mice.
- Partial restoration of T cell development at the DN3 stage was observed in SLP-76(-/-) Cbl(-/-) mice.
- A novel SLP-76- and Lck-independent ERK activation pathway, normally inhibited by c-Cbl, was identified.
Conclusions:
- c-Cbl plays a critical role in regulating T cell development and survival, particularly in the absence of SLP-76.
- The study uncovers a previously unknown signaling mechanism involving ERK activation that is modulated by c-Cbl.
- These findings provide new insights into the complex regulation of T cell signaling and development.
