Biology:CD154

Short description: Protein-coding gene in humans

Generic protein structure example

CD154, also called CD40 ligand or CD40L, is a protein that is primarily expressed on activated T cells and is a member of the TNF superfamily of molecules. It binds to CD40 on antigen-presenting cells (APC), which leads to many effects depending on the target cell type. In total CD40L has three binding partners: CD40, α5β1 integrin and integrin αIIbβ3. CD154 acts as a costimulatory molecule and is particularly important on a subset of T cells called T follicular helper cells (T_FH cells). On T_FH cells, CD154 promotes B cell maturation and function by engaging CD40 on the B cell surface and therefore facilitating cell-cell communication. A defect in this gene results in an inability to undergo immunoglobulin class switching and is associated with hyper IgM syndrome. Absence of CD154 also stops the formation of germinal centers and therefore prohibiting antibody affinity maturation, an important process in the adaptive immune system.

History

In 1991, three groups reported discovering CD154. Seth Lederman, Michael Yellin, and Leonard Chess at Columbia University generated a murine monoclonal antibody, 5c8, that inhibited contact-dependent T cell helper function in human cells and which characterized a 32 kDa surface protein transiently expressed on activated CD4+ T cells. Richard Armitage at Immunex cloned a cDNA encoding CD154 by screening an expression library with CD40-Ig. Randolph Noelle at Dartmouth Medical School generated an antibody that bound a 39 kDa protein on murine T cells and inhibited helper function. Noelle contested Lederman's patent, but the challenge (called an interference) was rejected on all counts

Expression

CD40 ligand (CD154) is primarily expressed on activated CD4+ T lymphocytes but is also found in a soluble form. While CD40L was originally described on T lymphocytes, its expression has since been found on a wide variety of cells, including platelets, mast cells, macrophages, basophils, NK cells, B lymphocytes, as well as non-haematopoietic cells (smooth muscle cells, endothelial cells, and epithelial cells).

Specific effects on cells

CD40L plays a central role in costimulation and regulation of the immune response via T cell priming and activation of CD40-expressing immune cells. At least 46 disease-causing mutations in this gene have been discovered.

Macrophages

In the macrophage, the primary signal for activation is IFN-γ from Th1 type CD4 T cells. The secondary signal is CD40L on the T cell, which binds CD40 on the macrophage cell surface. As a result, the macrophage expresses more CD40 and TNF receptors on its surface, which helps increase the level of activation. The activated macrophage can then destroy phagocytosed bacteria and produce more cytokines.

B cells

T cell-dependent B cell activation, showing a TH2-cell (left), B cell (right), and several interaction molecules, the TH2-cell expressing CD40L.

B cells can present antigens to a specialized group of helper T cells called T_FH cells. If an activated T_FH cell recognizes the peptide presented by the B cell, the CD40L on the T cell binds to the B cell's CD40, causing B cell activation. The T cell also produces IL-4, which directly influences B cells. As a result of this stimulation, the B cell can undergo rapid cellular division to form a germinal center where antibody isotype switching and affinity maturation occurs, as well as their differentiation to plasma cells and memory B cells. The end-result is a B cell that is able to mass-produce specific antibodies against an antigenic target. Early evidence for these effects were that in CD40 or CD154 deficient mice, there is little class switching or germinal centre formation, and immune responses are severely inhibited.

Endothelial cells

Activation of endothelial cells by CD40L (e.g. from activated platelets) leads to reactive oxygen species production, as well as chemokine and cytokine production, and expression of adhesion molecules such as E-selectin, ICAM-1, and VCAM-1. This inflammatory reaction in endothelial cells promotes recruitment of leukocytes to lesions and may potentially promote atherogenesis. CD40L has shown to be a potential biomarker for atherosclerotic instability.

Interactions

CD154 has been shown to interact with RNF128.

Further reading

• Parham, Peter (2004). The Immune System (2nd ed.). Garland Science. pp. 169–173. ISBN 0-8153-4093-1. https://archive.org/details/immunesystem00parh/page/169. 
• "CD40 and the effect of anti-CD40-binding on human multiple myeloma clonogenicity". Leukemia & Lymphoma 21 (1–2): 1–8. March 1996. doi:10.3109/10428199609067572. PMID 8907262. 
• "CD40-CD40 ligand". Journal of Leukocyte Biology 67 (1): 2–17. January 2000. doi:10.1002/jlb.67.1.2. PMID 10647992. 
• "CD40 ligand in CLL pathogenesis and therapy". Leukemia & Lymphoma 37 (5–6): 461–72. May 2000. doi:10.3109/10428190009058499. PMID 11042507. 
• "CD40:CD40L interactions in X-linked and non-X-linked hyper-IgM syndromes". Immunologic Research 24 (3): 311–24. 2002. doi:10.1385/IR:24:3:311. PMID 11817328. 
• "CD40 signaling and autoimmunity". Signal Transduction Pathways in Autoimmunity. Current Directions in Autoimmunity. 5. 2002. pp. 51–61. doi:10.1159/000060547. ISBN 3-8055-7308-1. 
• "CD154 and type-1 cytokine response: from hyper IgM syndrome to human immunodeficiency virus infection". The Journal of Infectious Diseases 185 (Suppl 1): S83-9. February 2002. doi:10.1086/338003. PMID 11865444. 
• "An expanding role for CD40L and other tumor necrosis factor superfamily ligands in HIV infection". Journal of Hematotherapy & Stem Cell Research 11 (5): 787–801. October 2002. doi:10.1089/152581602760404595. PMID 12427285. 
• "The role of CD40-CD154 interaction in cell immunoregulation". Journal of Biomedical Science 11 (4): 426–38. 2005. doi:10.1159/000077892. PMID 15153777. 
• Law, CL; Grewal, IS (2009). "Therapeutic Interventions Targeting CD40L (CD154) and CD40: The Opportunities and Challenges". Therapeutic Targets of the TNF Superfamily. Advances in Experimental Medicine and Biology. 647. pp. 8–36. doi:10.1007/978-0-387-89520-8_2. ISBN 978-0-387-89519-2. 

External links

• CD154+Antigen at the US National Library of Medicine Medical Subject Headings (MeSH)
• Human CD40LG genome location and CD40LG gene details page in the UCSC Genome Browser.
• GeneReviews/NCBI/NIH/UW entry on X-Linked Hyper IgM Syndrome or Immunodeficiency with Hyper-IgM, Type 1