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Antiproliferative action of interferon-alpha requires components of T-cell-receptor signalling
E F Petricoin1, S Ito, B L Williams
1Center for Biologics, Evaluation and Research, FDA, Bethesda, Maryland 20892, USA.
Abstract:
Signal transduction through both cytokine and lymphocyte antigen receptors shares some common pathways by which they initiate cellular responses, such as activation of mitogen-activated protein kinase(s). However, other signalling components appear to be uniquely coupled to each receptor. For example, the interferon receptors transduce regulatory signals through the JAK/STAT pathway, resulting in an inhibition of growth and of antiviral effects, whereas this pathway apparently plays no role in T-cell-receptor (TCR)-dependent gene expression. Conversely, signal transduction through the TCR requires the tyrosine kinases Lck and ZAP-70 and the tyrosine phosphatase CD45. Here we show that, unexpectedly, transmission of growth-inhibitory signals by interferon-alpha (IFN-alpha) in T cells requires the expression and association of CD45, Lck and ZAP-70 with the IFN-alpha-receptor signalling complex.
Insights
Interferon-alpha (IFN-alpha) uses T-cell receptor (TCR) signaling components like CD45, Lck, and ZAP-70 to inhibit T-cell growth. This unexpected finding reveals a shared pathway for cytokine and antigen receptor signaling.
Area of Science:
- Immunology
- Cellular Signaling
- Molecular Biology
Background:
- Cytokine and lymphocyte antigen receptors initiate cellular responses via common pathways like MAPK activation.
- Interferon receptors utilize the JAK/STAT pathway for growth inhibition and antiviral effects, distinct from T-cell receptor (TCR) signaling.
- TCR signaling involves specific tyrosine kinases (Lck, ZAP-70) and a tyrosine phosphatase (CD45).
Purpose of the Study:
- To investigate the signaling components involved in interferon-alpha (IFN-alpha)-mediated growth inhibition in T cells.
- To determine if TCR-associated signaling molecules play a role in IFN-alpha signal transduction.
Main Methods:
- Investigated the role of CD45, Lck, and ZAP-70 in IFN-alpha signaling.
- Examined the association of these molecules with the IFN-alpha receptor signaling complex in T cells.
Main Results:
- Demonstrated that IFN-alpha-induced growth inhibition in T cells unexpectedly requires the expression of CD45, Lck, and ZAP-70.
- Showed that these TCR signaling components associate with the IFN-alpha receptor signaling complex.
Conclusions:
- IFN-alpha utilizes key components of the TCR signaling pathway (CD45, Lck, ZAP-70) to mediate growth-inhibitory signals in T cells.
- This finding suggests a convergence of signaling pathways for cytokine receptors and antigen receptors in T cells.