CD154
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 αIIbβ3. CD154 acts as a costimulatory molecule and is particularly important on a subset of T cells called T follicular helper cells (TFH cells). On TFH 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.[1] Absence of CD154 also stops the formation of germinal centers and therefore prohibiting antibody affinity maturation, an important process in the adaptive immune system.
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).[2]
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
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. 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.[3] CD40L has shown to be a potential biomarker for atherosclerotic instability.[4]
Interactions
CD154 has been shown to interact with RNF128.[5]
References
- ↑ "Entrez Gene: CD40LG CD40 ligand (TNF superfamily, member 5, hyper-IgM syndrome)".
- ↑ Schönbeck U, Libby P (January 2001). "The CD40/CD154 receptor/ligand dyad". Cell. Mol. Life Sci. 58 (1): 4–43. doi:10.1007/PL00000776. PMID 11229815.
- ↑ 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. (March 2013). "CD40 ligand as a potential biomarker for atherosclerotic instability.". Neurol Res. 35 (7): 693–700. doi:10.1179/1743132813Y.0000000190. PMID 23561892.
- ↑ Lineberry NB, Su LL, Lin JT, Coffey GP, Seroogy CM, Fathman CG (Aug 2008). "Cutting Edge: The Transmembrane E3 Ligase GRAIL Ubiquitinates the Costimulatory Molecule CD40 Ligand during the Induction of T Cell Anergy". J. Immunol. 181 (3): 1622–6. doi:10.4049/jimmunol.181.3.1622. PMC 2853377. PMID 18641297.
External links
Further reading
- Parham, Peter (2004). The Immune System (2nd ed.). Garland Science. pp. 169–173. ISBN 0-8153-4093-1.
- Tong AW, Stone MJ (1997). "CD40 and the effect of anti-CD40-binding on human multiple myeloma clonogenicity". Leuk. Lymphoma 21 (1–2): 1–8. doi:10.3109/10428199609067572. PMID 8907262.
- van Kooten C, Banchereau J (2000). "CD40-CD40 ligand". J. Leukoc. Biol. 67 (1): 2–17. PMID 10647992.
- Schattner EJ (2003). "CD40 ligand in CLL pathogenesis and therapy". Leuk. 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". Immunol. Res. 24 (3): 311–24. doi:10.1385/IR:24:3:311. PMID 11817328.
- Cheng G, Schoenberger SP (2002). "CD40 signaling and autoimmunity". Curr. Dir. Autoimmun. Current Directions in Autoimmunity 5: 51–61. doi:10.1159/000060547. ISBN 3-8055-7308-1. PMID 11826760.
- Subauste CS (2002). "CD154 and type-1 cytokine response: from hyper IgM syndrome to human immunodeficiency virus infection". J. Infect. Dis. 185 Suppl 1: S83–9. doi:10.1086/338003. PMID 11865444.
- Kornbluth RS (2003). "An expanding role for CD40L and other tumor necrosis factor superfamily ligands in HIV infection". J. Hematother. Stem Cell Res. 11 (5): 787–801. doi:10.1089/152581602760404595. PMID 12427285.
- Xu Y, Song G (2005). "The role of CD40-CD154 interaction in cell immunoregulation". J. Biomed. Sci. 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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