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T-cell antigen receptor peptides inhibit signal transduction within the membrane bilayer
Xin M Wang1, Julianne T Djordjevic, Nozomu Kurosaka
1Department of Rheumatology, Westmead Hospital, Sydney, New South Wales, Australia.
Abstract:
Previous studies have shown that a synthetic peptide (core peptide, CP) corresponding to a 9-amino-acid region in the transmembrane domain of the alpha subunit of the T-cell antigen receptor (TCR) can suppress T-cell function in vitro and in vivo. The aim of these experiments was to determine the cellular site and molecular mechanism of CP inhibition in T cells. The cytochrome c-sensitive TCR-expressing hybridoma (2B4) was stimulated with pigeon cytochrome c antigen, anti-CD3 crosslinking, or PMA and ionomycin, in the presence or absence of CP, and the resulting IL-2 produced was measured in a bioassay using an IL-2-dependent cell line (CTLL-2). In the presence of CP, IL-2 production was inhibited following antigen-induced stimulation. By contrast, when stimulated with cross-linking antibodies to the CD3 complex or with PMA and ionomycin, both of which activate T cells downstream of the TCR antigen recognition site, CP had no effect on IL-2 production. These experiments suggest that CP interferes with TCR function by inhibiting T-cell activation at the transmembrane/receptor level. In addition, we show that CP inhibits early TCR signal transduction events such as TCR zeta chain phosphorylation following stimulation with either antigen or anti-CD3-crosslinking antibodies, although this is unlikely to be the mechanism leading to the reduced IL-2 production.
Insights
A synthetic core peptide (CP) inhibits T-cell activation by interfering with the T-cell receptor (TCR) at the cell surface. This peptide suppresses immune responses, offering potential therapeutic strategies for T-cell mediated diseases.
Area of Science:
- Immunology
- Molecular Biology
- Cell Signaling
Background:
- The T-cell receptor (TCR) is crucial for adaptive immunity.
- A synthetic peptide (core peptide, CP) is known to suppress T-cell function.
- The precise mechanism and cellular site of CP inhibition require elucidation.
Purpose of the Study:
- To determine the cellular site of action for the core peptide (CP).
- To elucidate the molecular mechanism by which CP inhibits T-cell activation.
- To investigate CP's effect on T-cell receptor (TCR) signaling.
Main Methods:
- Utilized a cytochrome c-sensitive TCR-expressing hybridoma (2B4) cell line.
- Stimulated T cells with pigeon cytochrome c antigen, anti-CD3 crosslinking, or PMA/ionomycin.
- Measured interleukin-2 (IL-2) production using a bioassay with CTLL-2 cells.
- Assessed TCR zeta chain phosphorylation as an early signaling event.
Main Results:
- CP inhibited IL-2 production following antigen-induced T-cell stimulation.
- CP did not affect IL-2 production when T cells were stimulated downstream of the TCR.
- CP inhibited early TCR signaling events like zeta chain phosphorylation, but this was not the primary cause of IL-2 suppression.
Conclusions:
- CP interferes with T-cell receptor (TCR) function by inhibiting T-cell activation at the transmembrane/receptor level.
- The findings suggest CP's potential as a modulator of T-cell immune responses.
- CP's mechanism involves disruption of early TCR signaling, impacting T-cell activation.