T cell‐specific gene targeting reveals that α4 is required for early T cell development
Open accessAbstract
Alpha4-mediated signaling is involved in a variety of functions in mammalian cells. To determine whether this is true for immunocompetent cells, we generated mutant (Lck-alpha4-) mice in which the alpha4 gene was deleted in a T cell-specific manner using the Cre/loxP system. These mice showed impaired early T cell development. Thymi at most ages were small and their architecture was disorganized. This defect was not due to increased thymocyte apoptosis but to decreased cell proliferation. T cell development was found to be severely arrested at the CD4/CD8 double-negative 3 stage and the thymus contained very few double-positive or single-positive (SP) mature thymocytes. The mutant thymocytes showed impaired proliferative responses to anti-CD3 monoclonal antibody (mAb) stimulation or to the cytokines IL-2, IL-1 or TNF. In the spleen, the numbers of mature SP T cells were decreased and their proliferative responses to anti-CD3 plus IL-2 or to anti-CD28 mAb were impaired. A severe impairment of CD3-induced expression of CD25 was also observed. These data suggest that alpha4 plays a critical role in the proliferation of thymocytes, which is necessary for early T cell development.
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Thymocytes showed decreased cytokine- and anti-CD3-induced proliferation capacity but no increased apoptosis, and impaired CD3 signaling, exemplified by a lack of anti-CD3-induced IL-2R expression while anti-CD3-induced CD28 expression was normal.
“Thymocytes showed a decreased cytokine-and anti-CD3-induced proliferation capacity but no increased apoptosis, and impaired CD3 signaling, exemplified by a lack of anti-CD3-induced IL-2R expression, while anti-CD3-induced CD28 expression was normal.”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [88]
T-cell development was arrested at the CD4/CD8 double-negative 3 stage.
“T-cell development was arrested at the CD4/CD8 doublenegative 3 stage.”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [88]
T-cell-specific knockout of α4 caused impaired early T-cell development associated with smaller and disorganized thymi.
“Impaired early T-cell development, associated with smaller and disorganized thymi, was the main phenotype in T-cell-specific KO mice of α4 [88].”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [88]
In these mice, CD3 signaling in thymocytes is impaired.
“-impaired CD3 signaling in thymocytes”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [88]
In these mice, thymocytes do not show increased apoptosis.
“-Decreased proliferation capacity, but no increased apoptosis of | thymocytes”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [88]
In mice with T-cell-specific conditional knockout of Igbp1 (Lck-Cre), early T-cell development is impaired.
“-Impaired early T-cell development [88]”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [88]
In these mice, thymocytes have decreased proliferation capacity.
“-Decreased proliferation capacity, but no increased apoptosis of | thymocytes”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [88]
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References 34 · Cited by 16
- Authors
- Hua, D. R., Inui, S., Yamashita, T., Maeda, K., Takagi, K., Takeda, J., & Sakaguchi, N.
- Affiliations
- Kumamoto University (JP)
- The University of Osaka (JP)
- Corresponding author
- Sakaguchi, Nobuo
- Venue
- European Journal of Immunology
- Publisher
- Wiley
- Published
- 2003-06-10
- Volume
- 33
- Issue
- 7
- Pages
- 1899-1906
- ISSN
- 0014-2980 (ISSN-L)
- 1521-4141
- OpenAlex
- W1990049897
- Cited by
- 16
- References
- 34
- Citations by year
- 2021: 1 · 2018: 1 · 2014: 1 · 2013: 1 · 2012: 1
- FWCI
- 0.66
- Type
- journal article
- Language
- en
- Open access
- Licence
- Locations
- European Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Kumamoto University Repository (Kumamoto University) (submittedVersion, cc-by-nc-nd)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- CD49d, T cell development, thymocyte proliferation, thymus, CD4+CD8+ double-negative thymocytes, CD3 signaling, interleukin-2, CD28, CD25 expression, integrin signaling
- MeSH terms
- Animals, Cell Differentiation, Cell Division, Mutation, Phosphoproteins, Spleen, T-Lymphocytes, Thymus Gland, Signal Transduction, CD3 Complex, Gene Targeting, Molecular Chaperones, Intercellular Signaling Peptides and Proteins, Adaptor Proteins, Signal Transducing, Mice
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