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Negative regulation of human T cell activation by the receptor-type protein tyrosine phosphatase CD148
1Immunobiology Department, DNAX Research Institute of Molecular and Cellular Biology, Palo Alto, CA 94304, USA. tangye@dnax.org
Abstract:
T cell activation represents a balance between positive and negative signals delivered via distinct cell surface molecules. Many cytoplasmic protein tyrosine phosphatases are involved in regulating cellular responses by antagonizing the action of protein tyrosine kinases. CD148 is a receptor-type protein tyrosine phosphatase expressed by all human mononuclear cells. We have investigated the effect of CD148 on TCR-mediated activation of human T cells. Overexpression of wild-type, but not a phosphatase-deficient, CD148 in Jurkat T cells inhibited TCR-mediated activation, evidenced by reduced expression of the early activation Ag CD69, inhibition of tyrosine phosphorylation of many intracellular proteins including the critical protein tyrosine kinase ZAP-70, and impairment of mitogen-activated protein kinase activation. Taken together, these results suggest that CD148 is an important phosphatase involved in negatively regulating the proximal signaling events during activation of Ag-specific T cells.
Insights
CD148, a protein tyrosine phosphatase, negatively regulates T cell activation. Overexpressing CD148 in T cells reduced activation signals, indicating its role in immune response control.
Area of Science:
- Immunology
- Cell Biology
- Biochemistry
Background:
- T cell activation relies on a balance of positive and negative signals.
- Protein tyrosine phosphatases counteract protein tyrosine kinases in cellular signaling.
- CD148 is a receptor-type protein tyrosine phosphatase found on human mononuclear cells.
Purpose of the Study:
- To investigate the role of CD148 in T cell receptor (TCR)-mediated activation of human T cells.
- To determine if CD148's phosphatase activity is essential for its regulatory function.
Main Methods:
- Overexpression of wild-type and phosphatase-deficient CD148 in Jurkat T cells.
- Analysis of TCR-mediated activation markers, including CD69 expression.
- Assessment of intracellular protein tyrosine phosphorylation, focusing on ZAP-70.
- Evaluation of mitogen-activated protein kinase (MAPK) pathway activation.
Main Results:
- Overexpression of wild-type CD148 inhibited TCR-mediated T cell activation.
- This inhibition was evidenced by reduced CD69 expression and impaired MAPK activation.
- Phosphatase-deficient CD148 did not inhibit T cell activation, and tyrosine phosphorylation of ZAP-70 was reduced.
- These findings highlight CD148's phosphatase activity in regulating proximal signaling.
Conclusions:
- CD148 acts as a negative regulator of T cell activation.
- Its phosphatase activity is crucial for inhibiting early signaling events during T cell activation.
- CD148 plays a significant role in controlling antigen-specific T cell responses.