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ICOS costimulation requires IL-2 and can be prevented by CTLA-4 engagement
J L Riley1, P J Blair, J T Musser
1Abramson Family Cancer Research Institute and Department of Molecular and Cellular Engineering, University of Pennsylvania, Philadelphia, PA 19104, USA. rileyj@mail.med.upenn.edu
Journal of Immunology (Baltimore, Md. : 1950)
|April 6, 2001
Summary
Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) engagement blocks Inducible T-cell costimulator (ICOS) costimulation. Interleukin-2 (IL-2) overcomes these blocks and enhances T-cell activation, indicating synergy.
Area of Science:
- Immunology
- Molecular Biology
- Cell Biology
Background:
- Costimulatory receptors like ICOS and CD28 are crucial for T-cell activation.
- CTLA-4 is a known inhibitory receptor that regulates T-cell responses.
- Understanding the interplay between these receptors is vital for immune response modulation.
Purpose of the Study:
- To investigate the relationship between ICOS, CD28, CTLA-4, and IL-2 in T-cell costimulation.
- To elucidate the mechanisms by which CTLA-4 influences ICOS-mediated costimulation.
- To explore the role of IL-2 in overcoming CTLA-4-mediated inhibition of ICOS signaling.
Main Methods:
- Utilized magnetic beads coated with anti-CD3, anti-ICOS, and anti-CTLA-4 antibodies.
- Assessed T-cell proliferation and cytokine production (IL-4, IL-10, IL-13) under varying conditions.
- Investigated both indirect (affecting ICOS expression) and direct (downstream signaling) mechanisms of CTLA-4 action.
- Examined the effects of IL-2 addition on ICOS costimulation and T-cell activation.
Main Results:
- CTLA-4 ligation was shown to inhibit ICOS costimulation, blocking T-cell proliferation and production of IL-4, IL-10, and IL-13.
- CTLA-4 exerted its inhibitory effects through both indirect mechanisms (reducing ICOS surface expression) and direct mechanisms (interfering with downstream signaling).
- Addition of IL-2 effectively overcame CTLA-4-mediated inhibition and significantly augmented T-cell activation, demonstrating synergy between ICOS and IL-2 signaling.
- A minimum level of IL-2 was found to be necessary for T-cell proliferation, and exogenous IL-2 was required for sustained growth of ICOS-costimulated T cells.
Conclusions:
- CTLA-4 plays a critical role in the stringent control of ICOS costimulation.
- CTLA-4 engagement initially limits ICOS costimulation by affecting ICOS expression and downstream signaling.
- IL-2 signaling is essential for overcoming CTLA-4-mediated suppression and is required for sustained T-cell activation, highlighting a cooperative relationship between ICOS and IL-2 pathways.