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Published on: September 30, 2010
Hyper-reactive cloned mice generated by direct nuclear transfer of antigen-specific CD4+ T cells
Osamu Kaminuma1,2,3,4, Kazufumi Katayama5, Kimiko Inoue2
1Allergy and Immunology Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan osamuk@yamanashi.ac.jp ogura@rtc.riken.go.jp.
Abstract:
T-cell receptor (TCR)-transgenic mice have been employed for evaluating antigen-response mechanisms, but their non-endogenous TCR might induce immune response differently than the physiologically expressed TCR Nuclear transfer cloning produces animals that retain the donor genotype in all tissues including germline and immune systems. Taking advantage of this feature, we generated cloned mice that carry endogenously rearranged TCR genes from antigen-specific CD4+ T cells. We show that T cells of the cloned mice display distinct developmental pattern and antigen reactivity because of their endogenously pre-rearranged TCRα (rTα) and TCRβ (rTβ) alleles. These alleles were transmitted to the offspring, allowing us to establish a set of mouse lines that show chronic-type allergic phenotypes, that is, bronchial and nasal inflammation, upon local administrations of the corresponding antigens. Intriguingly, the existence of either rTα or rTβ is sufficient to induce in vivo hypersensitivity. These cloned mice expressing intrinsic promoter-regulated antigen-specific TCR are a unique animal model with allergic predisposition for investigating CD4+ T-cell-mediated pathogenesis and cellular commitment in immune diseases.
Insights
Cloned mice with endogenously rearranged T-cell receptors (TCRs) exhibit altered T-cell development and reactivity. These mice develop chronic allergic conditions, demonstrating the utility of this model for studying T-cell-mediated immune diseases.
Area of Science:
- Immunology
- Genetics
- Allergy Research
Background:
- T-cell receptor (TCR)-transgenic mice are used to study immune responses, but non-endogenous TCRs may not fully replicate physiological responses.
- Nuclear transfer cloning allows for the generation of animals with donor genotypes in all tissues, including the immune system.
Purpose of the Study:
- To generate cloned mice with endogenously rearranged TCR genes from antigen-specific CD4+ T cells.
- To investigate the impact of endogenously pre-rearranged TCRα (rTα) and TCRβ (rTβ) alleles on T-cell development, antigen reactivity, and allergic phenotypes.
Main Methods:
- Generation of cloned mice using nuclear transfer with DNA from antigen-specific CD4+ T cells.
- Analysis of T-cell development and antigen reactivity in cloned mice.
- Assessment of allergic phenotypes (bronchial and nasal inflammation) upon antigen administration.
- Evaluation of the inheritance of rTα and rTβ alleles in offspring.
Main Results:
- Cloned mice exhibited distinct T-cell developmental patterns and antigen reactivity due to endogenously rearranged TCRα (rTα) and TCRβ (rTβ) alleles.
- These mice developed chronic allergic phenotypes, including bronchial and nasal inflammation, after local antigen administration.
- The presence of either rTα or rTβ alone was sufficient to induce in vivo hypersensitivity.
Conclusions:
- Cloned mice expressing intrinsic promoter-regulated, antigen-specific TCRs provide a unique model for studying CD4+ T-cell-mediated pathogenesis.
- This model demonstrates allergic predisposition and is valuable for investigating cellular commitment in immune diseases.
- The findings highlight the role of endogenous TCR rearrangement in T-cell function and allergic disease development.
