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The CD40/CD154 receptor/ligand dyad
1Cardiovascular Medicine, Department of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA. uschoenbeck@rics.bwh.harward.edu
Insights
The CD40/CD154 interaction, once thought limited to lymphocytes, is now known to involve many cell types. This signaling pathway plays a crucial role in immune regulation and various human diseases.
Area of Science:
- Immunology
- Cell Biology
- Molecular Medicine
Background:
- The CD40 receptor and its ligand CD154 were traditionally considered to function primarily in lymphocyte communication for humoral immune responses.
- Emerging evidence indicates broader expression and function beyond lymphocytes.
Purpose of the Study:
- To review the synthesis and structure of CD40.
- To outline CD154/CD40 signaling pathways.
- To emphasize the expanded role of the CD40/CD154 dyad in immunoregulatory processes and human diseases.
Main Methods:
- Literature review focusing on CD40/CD154 expression and function.
- Synthesis of current research on CD40/CD154 signaling pathways.
- Analysis of CD40/CD154 involvement in various diseases.
Main Results:
- CD40 and CD154 are expressed on a wide range of non-lymphocytic cells, including myeloid and non-hematopoietic cells.
- CD40 ligation triggers diverse immune and inflammatory responses (e.g., adhesion molecules, cytokines, apoptosis).
- CD40 signaling is implicated in the pathogenesis of chronic inflammatory conditions.
Conclusions:
- The CD40/CD154 dyad is a critical mediator beyond lymphocyte interactions.
- Its role extends to diverse immunoregulatory functions.
- Understanding CD40/CD154 signaling is vital for addressing numerous prevalent human diseases.
Abstract:
Until recently, the expression and primary function of the cell surface receptor CD40 and its ligand CD154 were considered restricted to B and T lymphocytes, and their interactions required for the thymus-dependent humoral response. However, current work from several groups challenges this view of the CD40/CD154 dyad as a mere mediator of lymphocyte communication. A variety of non-lymphocytic cell types express both receptor and ligand, including hematopoetic and non-hematopoetic cells, such as monocytes, basophils, eosinophils, dendritic cells, fibroblasts, smooth muscle, and endothelial cells. Accordingly, ligation of CD40 mediates a broad variety of immune and inflammatory responses, such as the expression of adhesion molecules, cytokines, matrix-degrading enzymes, prothrombotic activities, and apoptotic mediators. Consequently, CD40 signaling has been associated with pathogenic processes of chronic inflammatory diseases, such as autoimmune diseases, neurodegenerative disorders, graft-versus-host disease, cancer, and atherosclerosis. This review focuses on the synthesis and structure of CD40 and outlines CD154/CD40 signaling pathways, and emphasizes the previously unexpected importance of the CD40/CD154 receptor/ligand dyad in a spectrum of immunoregulatory processes and prevalent human diseases.