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Disruption of lymphocyte function and signaling in CD45-associated protein-null mice
A Matsuda1, S Motoya, S Kimura
1Department of Pathology, Roger Williams Hospital-Brown University, Providence, Rhode Island 02908, USA.
Abstract:
CD45-AP specifically associates with CD45, a protein tyrosine phosphatase essential for lymphocyte differentiation and antigen receptor-mediated signal transduction. CD45 is thought to mediate antigen receptor signaling by dephosphorylating regulatory tyrosine residues on Src family protein tyrosine kinases such as Lck. However, the mechanism for regulating CD45 protein tyrosine phosphatase activity remains unclear. CD45-AP-null mice were created to examine the role of CD45-AP in CD45-mediated signal transduction. T and B lymphocytes showed reduced proliferation in response to antigen receptor stimulation. Both mixed leukocyte reaction and cytotoxic T lymphocyte functions of T cells were also markedly decreased in CD45-AP-null mice. Interestingly, the interaction between CD45 and Lck was significantly reduced in CD45-AP-null T cells, indicating that CD45-AP directly or indirectly mediates the interaction of CD45 with Lck. Our data indicate that CD45-AP is required for normal antigen receptor signaling and function in lymphocytes.
Insights
CD45-AP is crucial for lymphocyte function, as CD45-AP-null mice exhibit impaired T and B cell proliferation and reduced cytotoxic T lymphocyte activity. This protein mediates CD45 interaction with Lck, essential for signaling.
Area of Science:
- Immunology
- Molecular Biology
- Cell Signaling
Background:
- CD45, a protein tyrosine phosphatase, is vital for lymphocyte development and antigen receptor signaling.
- CD45 regulates Src family kinases like Lck, but its activity regulation is not fully understood.
Purpose of the Study:
- To investigate the role of CD45-AP in CD45-mediated signal transduction using CD45-AP-null mice.
- To elucidate the mechanism by which CD45 protein tyrosine phosphatase activity is regulated.
Main Methods:
- Generation and analysis of CD45-AP-null mice.
- Assessment of lymphocyte proliferation in response to antigen receptor stimulation.
- Evaluation of mixed leukocyte reaction and cytotoxic T lymphocyte functions.
- Analysis of CD45 and Lck interaction in T cells.
Main Results:
- CD45-AP-null mice displayed significantly reduced proliferation in T and B lymphocytes.
- Impaired mixed leukocyte reaction and cytotoxic T lymphocyte functions were observed in CD45-AP-null mice.
- The interaction between CD45 and Lck was markedly reduced in CD45-AP-null T cells.
Conclusions:
- CD45-AP plays a critical role in regulating CD45-mediated signal transduction.
- CD45-AP is essential for normal antigen receptor signaling and function in lymphocytes.
- CD45-AP directly or indirectly mediates the interaction between CD45 and Lck.