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A point mutation in the extracellular domain of CD4 completely abolishes CD4 T cell development in C57BL/6 mouse
Huijie Wang1, Saichao Li1, Tianzhu Chao2
1Laboratory of Genetic Regulators in the Immune System, School of Laboratory Medicine, Xinxiang Medical University, Henan Province 453003, China; Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, Xinxiang Medical University, Xinxiang, Henan, China; Xinxiang Assegai Medical Laboratory Institute, Xinxiang, Henan, China.
Abstract:
In this study, we performed ENU mutagenesis and multi-parameter flow cytometric analysis in C57BL/6 mice to uncover novel genes or alleles regulating immune cell development. We identified a novel mutant allele of Cd4 gene which completely blocked development of a major subset of T cells named CD4 T cell. Our data for the first time showed experimentally in mice the critical role of the first extracellular domain, by obtaining mice with a loss of function mutation from Ile to Asn at the position 99 of CD4 (I99N). Interestingly, such CD4I99N mutant protein can be expressed on the surface of human cells, and the mRNA stability could be also affected by this point mutation, suggesting that absence of CD4 T cells in mice rooted in the deficiency in function and expression of CD4. In addition, we used this novel CD4 T cell deficient model as recipient mice for adoptive transfer experiment, and showed that it could be an optimal model for study of CD4 T cells.
Insights
Researchers discovered a new mutation in the Cd4 gene (CD4) that blocks CD4 T cell development in mice. This finding highlights the importance of the CD4 protein
Area of Science:
- Immunology
- Genetics
- Molecular Biology
Background:
- Immune cell development is regulated by complex genetic factors.
- CD4 T cells are crucial for adaptive immunity.
- Understanding CD4 gene function is vital for immune system research.
Purpose of the Study:
- To identify novel genes and alleles controlling immune cell development using ENU mutagenesis.
- To investigate the function of the CD4 gene and its extracellular domains.
- To establish a mouse model for studying CD4 T cell deficiency.
Main Methods:
- ENU mutagenesis in C57BL/6 mice.
- Multi-parameter flow cytometry for immune cell analysis.
- Generation and characterization of a novel Cd4 mutant allele (CD4 I99N).
Main Results:
- A novel mutant allele of the Cd4 gene (CD4 I99N) was identified, completely blocking CD4 T cell development.
- The mutation (Ile to Asn at position 99) affects the first extracellular domain of CD4.
- The CD4 I99N mutation impacts protein expression and mRNA stability, leading to CD4 T cell absence.
- The CD4-deficient mice serve as an optimal model for adoptive transfer experiments.
Conclusions:
- The first extracellular domain of CD4 is critical for T cell development.
- The CD4 I99N mutation provides experimental evidence for CD4's role in immune cell development.
- This study establishes a valuable mouse model for investigating CD4 T cell biology and related immune responses.
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