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Interactions of thrombospondins with alpha4beta1 integrin and CD47 differentially modulate T cell behavior
Zhuqing Li1, Maria J Calzada, John M Sipes
1Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-1500, USA.
The Journal of Cell Biology
|May 1, 2002
Summary
Thrombospondin (TSP)-1 differentially modulates T cell responses through two receptors: integrin alpha4beta1 and CD47. Receptor engagement dictates whether TSP1 stimulates or inhibits T cell functions like adhesion and proliferation.
Area of Science:
- Immunology
- Molecular Biology
- Cell Biology
Background:
- Thrombospondin (TSP)-1 is known to influence T cell behavior, exhibiting both positive and negative modulatory effects.
- The mechanisms underlying these opposing T cell responses to TSP-1 are not fully understood.
Purpose of the Study:
- To elucidate the distinct roles of T cell receptors in mediating TSP-1's dual effects on T cell function.
- To identify the specific TSP-1 domains and receptor interactions responsible for differential T cell modulation.
Main Methods:
- Investigated TSP-1 interactions with T cell receptors, specifically integrin alpha4beta1 and CD47.
- Utilized recombinant TSP-2 fragments to assess conserved recognition sites.
- Examined the impact of TSP-1 on T cell adhesion, chemotaxis, gene expression, proliferation, and T cell receptor signaling.
Main Results:
- Integrin alpha4beta1 recognizes an LDVP sequence in TSP-1, mediating T cell adhesion, chemotaxis, and MMP gene expression.
- TSP-1 binding to alpha4beta1 is dependent on integrin activation state and inhibits alpha4beta1 interaction with VCAM-1.
- CD47, a second TSP-1 receptor, is crucial for TSP-1's T cell receptor antagonist and antiproliferative activities, while not essential for all stimulatory responses.
Conclusions:
- Differential engagement of integrin alpha4beta1 and CD47 by TSP-1 dictates opposing T cell responses.
- The alpha4beta1 integrin recognition site is conserved in TSP-2, mediating similar activities.
- Modulating the expression or function of these TSP receptors offers a potential strategy to control T cell responses to TSPs.