| CD40 ligand |
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PDB rendering based on 1aly.
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| Available structures |
| PDB |
Ortholog search: PDBe, RCSB |
| List of PDB id codes |
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1ALY, 1I9R, 3LKJ, 3QD6
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| Identifiers |
| Symbols |
CD40LG ; CD154; CD40L; HIGM1; IGM; IMD3; T-BAM; TNFSF5; TRAP; gp39; hCD40L |
| External IDs |
OMIM: 300386 MGI: 88337 HomoloGene: 56 GeneCards: CD40LG Gene |
| Gene ontology |
| Molecular function |
• cytokine activity
• tumor necrosis factor receptor binding
• CD40 receptor binding
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| Cellular component |
• extracellular space
• plasma membrane
• integral component of plasma membrane
• external side of plasma membrane
• integral component of membrane
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| Biological process |
• inflammatory response
• leukocyte cell-cell adhesion
• platelet activation
• B cell differentiation
• positive regulation of interleukin-12 production
• B cell proliferation
• negative regulation of apoptotic process
• isotype switching
• immunoglobulin secretion
• regulation of immune response
• regulation of immunoglobulin secretion
• positive regulation of endothelial cell apoptotic process
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| Sources: Amigo / QuickGO |
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| RNA expression pattern |
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| More reference expression data |
| Orthologs |
| Species |
Human |
Mouse |
| Entrez |
959 |
21947 |
| Ensembl |
ENSG00000102245 |
ENSMUSG00000031132 |
| UniProt |
P29965 |
P27548 |
| RefSeq (mRNA) |
NM_000074 |
NM_011616 |
| RefSeq (protein) |
NP_000065 |
NP_035746 |
| Location (UCSC) |
Chr X:
136.65 – 136.66 Mb |
Chr X:
57.21 – 57.22 Mb |
| PubMed search |
[1] |
[2] |
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CD154, also called CD40 ligand or CD40L, is a protein that is primarily expressed on activated T cells[1] 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 αIIbβ3. CD154 acts as a costimulatory molecule and is particularly important on a subset of T cells called T follicular helper cells (TFH cells).[2] On TFH cells, CD154 promotes B cell maturation and function by engaging CD40 on the B cell surface and therefore facilitating cell-cell communication.[3] A defect in this gene results in an inability to undergo immunoglobulin class switching and is associated with hyper IgM syndrome.[4] Absence of CD154 also stops the formation of germinal centers and therefore prohibiting antibody affinity maturation, an important process in the adaptive immune system.
Contents
- 1 History
- 2 Expression
- 3 Specific effects on cells
- 3.1 Macrophages
- 3.2 B cells
- 3.3 Endothelial cells
- 4 Interactions
- 5 References
- 6 External links
- 7 Further reading
- 8 External links
History
In 1991, three groups reported discovering CD154. Seth Lederman at Columbia University generated an murine monoclonal antibody, 5c8 that inhibited contact-dependent T cell helper function in human cells which characterized the 32 kDa surface protein transiently expressed on CD4+ T cells.[5] Richard Armitage at Immunex cloned a cDNA encoding CD154 by screening an expression library with CD40-Ig.[6] Randolph Noelle at Dartmouth Medical School generated an antibody that bound a 39 kDa protein on murine T cells and inhibited helper function.[7]
Expression
CD40 ligand 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).[8]
Specific effects on cells
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 TFH cells. If an activated TFH 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.[9] 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.[10] CD40L has shown to be a potential biomarker for atherosclerotic instability.[11]
Interactions
CD154 has been shown to interact with RNF128.[12]
References
- ^ Lederman S, Yellin MJ, Krichevsky A, Belko J, Lee JJ, Chess L (April 1992). "Identification of a novel surface protein on activated CD4+ T cells that induces contact-dependent B cell differentiation (help)". The Journal of Experimental Medicine 175 (4): 1091–101. doi:10.1084/jem.175.4.1091. PMC: 2119166. PMID 1348081.
- ^ Lederman S, Yellin MJ, Inghirami G, Lee JJ, Knowles DM, Chess L (December 1992). "Molecular interactions mediating T-B lymphocyte collaboration in human lymphoid follicles. Roles of T cell-B-cell-activating molecule (5c8 antigen) and CD40 in contact-dependent help". Journal of Immunology 149 (12): 3817–26. PMID 1281189.
- ^ Lederman S, Yellin MJ, Cleary AM, Pernis A, Inghirami G, Cohn LE, Covey LR, Lee JJ, Rothman P, Chess L (March 1994). "T-BAM/CD40-L on helper T lymphocytes augments lymphokine-induced B cell Ig isotype switch recombination and rescues B cells from programmed cell death". Journal of Immunology 152 (5): 2163–71. PMID 7907632.
- ^ "Entrez Gene: CD40LG CD40 ligand (TNF superfamily, member 5, hyper-IgM syndrome)".
- ^ Lederman S, Yellin MJ, Krichevsky A, Belko J, Lee JJ, Chess L (April 1992). "Identification of a novel surface protein on activated CD4+ T cells that induces contact-dependent B cell differentiation (help)". The Journal of Experimental Medicine 175 (4): 1091–101. doi:10.1084/jem.175.4.1091. PMC: 2119166. PMID 1348081.
- ^ Armitage RJ, Fanslow WC, Strockbine L, Sato TA, Clifford KN, Macduff BM, Anderson DM, Gimpel SD, Davis-Smith T, Maliszewski CR, et al. (May 1992). "Molecular and biological characterization of a murine ligand for CD40". Nature 357 (6373): 80–2. PMID 1374165.
- ^ Noelle RJ, Roy M, Shepherd DM, Stamenkovic I, Ledbetter JA, Aruffo A (July 1992). "A 39-kDa protein on activated helper T cells binds CD40 and transduces the signal for cognate activation of B cells". Proc Natl Acad Sci U S A 89 (14): 6550–4. PMID 1378631.
- ^ Schönbeck U, Libby P (January 2001). "The CD40/CD154 receptor/ligand dyad". Cellular and Molecular Life Sciences 58 (1): 4–43. doi:10.1007/PL00000776. PMID 11229815.
- ^ Cleary AM, Fortune SM, Yellin MJ, Chess L, Lederman S (October 1995). "Opposing roles of CD95 (Fas/APO-1) and CD40 in the death and rescue of human low density tonsillar B cells". Journal of Immunology 155 (7): 3329–37. PMID 7561026.
- ^ Szmitko PE, Wang CH, Weisel RD, de Almeida JR, Anderson TJ, Verma S (October 2003). "New markers of inflammation and endothelial cell activation: Part I". Circulation 108 (16): 1917–23. doi:10.1161/01.CIR.0000089190.95415.9F. PMID 14568885.
- ^ Wang JH, Zhang YW, Zhang P, Deng BQ, Ding S, Wang ZK, Wu T, Wang J (September 2013). "CD40 ligand as a potential biomarker for atherosclerotic instability". Neurological Research 35 (7): 693–700. doi:10.1179/1743132813Y.0000000190. PMID 23561892.
- ^ Lineberry NB, Su LL, Lin JT, Coffey GP, Seroogy CM, Fathman CG (August 2008). "Cutting edge: The transmembrane E3 ligase GRAIL ubiquitinates the costimulatory molecule CD40 ligand during the induction of T cell anergy". Journal of Immunology 181 (3): 1622–6. doi:10.4049/jimmunol.181.3.1622. PMC: 2853377. PMID 18641297.
External links
- GeneReviews/NCBI/NIH/UW entry on X-Linked Hyper IgM Syndrome or Immunodeficiency with Hyper-IgM, Type 1
Further reading
- Parham, Peter (2004). The Immune System (2nd ed.). Garland Science. pp. 169–173. ISBN 0-8153-4093-1.
- Tong AW, Stone MJ (March 1996). "CD40 and the effect of anti-CD40-binding on human multiple myeloma clonogenicity". Leukemia & Lymphoma 21 (1-2): 1–8. doi:10.3109/10428199609067572. PMID 8907262.
- van Kooten C, Banchereau J (January 2000). "CD40-CD40 ligand". Journal of Leukocyte Biology 67 (1): 2–17. PMID 10647992.
- Schattner EJ (May 2000). "CD40 ligand in CLL pathogenesis and therapy". Leukemia & Lymphoma 37 (5-6): 461–72. doi:10.3109/10428190009058499. PMID 11042507.
- Bhushan A, Covey LR (2002). "CD40:CD40L interactions in X-linked and non-X-linked hyper-IgM syndromes". Immunologic Research 24 (3): 311–24. doi:10.1385/IR:24:3:311. PMID 11817328.
- Cheng G, Schoenberger SP (2002). "CD40 signaling and autoimmunity". Current Directions in Autoimmunity. Current Directions in Autoimmunity 5: 51–61. doi:10.1159/000060547. ISBN 3-8055-7308-1. PMID 11826760.
- Subauste CS (February 2002). "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. doi:10.1086/338003. PMID 11865444.
- Kornbluth RS (October 2002). "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. doi:10.1089/152581602760404595. PMID 12427285.
- Xu Y, Song G (2005). "The role of CD40-CD154 interaction in cell immunoregulation". Journal of Biomedical Science 11 (4): 426–38. doi:10.1159/000077892. PMID 15153777.
External links
- CD154 Antigen at the US National Library of Medicine Medical Subject Headings (MeSH)
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PDB gallery
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1aly: CRYSTAL STRUCTURE OF HUMAN CD40 LIGAND
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1i9r: STRUCTURE OF CD40L IN COMPLEX WITH THE FAB FRAGMENT OF HUMANIZED 5C8 ANTIBODY
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Cell signaling: cytokines
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