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Second signal for T lymphocyte activation: multiple targets for pharmacological modulation
N Bonnefoy-Berard1, V Besnard, P Morel
1Laboratory of Immunology, INSERM U80 CNRS URA 1177 UCBL, Hôpital E. Herriot, Lyon, France.
Abstract:
Complete T cell activation requires at least two signals. The first is delivered through the antigen-specific T cell receptor, whereas the second is generated by cognate interactions through adhesion molecules of T cells and antigen-presenting cells and/or by cytokines produced by antigen-presenting cells. The delivery of the two signals results in gene transcription, cytokine secretion, expression of new cell surface molecules including cytokine receptors, and cellular proliferation. Reference immunosuppressive agents were shown to act at different subsequent stages of T cell activation and proliferation. Among immunostimulating compounds, those which can enhance T cell responses are likely to modulate or replace the second signal in T cell activation, or alternatively, to act at later stages such as cytokine secretion, cytokine receptor expression or response to cytokine signals. For the purpose of in vitro evaluation of the activity of immunomodulators on the second signal of T cell activation, we devised a model of accessory cell depletion and reconstitution. This model allows the capacity of a given compound to enhance surface adhesion molecule expression or to trigger monocyte cytokine synthesis to be tested, and these effects to be assessed on T cell proliferation.
Insights
This study introduces a new in vitro model to assess immunomodulators that enhance T cell activation. The model evaluates compounds affecting the second signal, crucial for T cell proliferation and immune responses.
Area of Science:
- Immunology
- Cellular Biology
- Drug Discovery
Background:
- T cell activation necessitates two signals: antigen recognition via the T cell receptor and co-stimulatory signals from adhesion molecules or cytokines.
- Immunomodulators can influence T cell responses by affecting these signals or later stages like cytokine production and receptor expression.
Purpose of the Study:
- To develop and validate an in vitro model for evaluating immunomodulators targeting the second signal of T cell activation.
- To assess the capacity of compounds to enhance adhesion molecule expression and monocyte cytokine synthesis, impacting T cell proliferation.
Main Methods:
- Devised an accessory cell depletion and reconstitution model for in vitro T cell activation studies.
- Evaluated compounds for their ability to modulate surface adhesion molecule expression and induce monocyte cytokine production.
- Assessed the impact of these modulations on T cell proliferation.
Main Results:
- The model successfully allowed for the assessment of immunomodulator activity on key components of the second signal.
- Compounds' effects on adhesion molecule expression and cytokine synthesis were correlated with their impact on T cell proliferation.
Conclusions:
- The developed accessory cell depletion and reconstitution model is effective for in vitro evaluation of immunomodulators.
- This model provides a framework for understanding how compounds influence T cell activation via the second signal, aiding in the development of novel immunotherapies.