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 (protein) 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.
In 1991, three groups reported discovering CD154. Seth Lederman at Columbia University generated a 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] Noelle contested Lederman's patent, but the challenge (called an interference) was rejected on all counts [8]
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).[9]
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.[10]
Macrophages
In the macrophage, the primary signal for activation is IFN-γ from Th1 type CD4T 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
File:T-dependent B cell activation.pngT 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.[11] 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 antibodyisotype 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.[12]
↑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. PMID1281189.
↑"Patent 5,474,771"(PDF). UNITED STATES PATENT AND TRADEMARK OFFICE. U.S. Patent Office.
↑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. PMID11229815.
↑Grewal, IS; Xu, J; Flavell, RA (7 December 1995). "Impairment of antigen-specific T-cell priming in mice lacking CD40 ligand". Nature. 378: 617–20. doi:10.1038/378617a0. PMID8524395.
↑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. PMID14568885.
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van Kooten C, Banchereau J (January 2000). "CD40-CD40 ligand". Journal of Leukocyte Biology. 67 (1): 2–17. PMID10647992.
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. PMID11817328.
Cheng G, Schoenberger SP (2002). "CD40 signaling and autoimmunity". Current Directions in Autoimmunity. Current Directions in Autoimmunity. 5: 51–61. doi:10.1159/000060547. ISBN3-8055-7308-1. PMID11826760.
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. PMID11865444.
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. PMID12427285.
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. PMID15153777.
Law, CL; Grewal, IS (2009). "Therapeutic interventions targeting CD40L (CD154) and CD40: the opportunities and challenges". Advances in Experimental Medicine and Biology. 647: 8–36. doi:10.1007/978-0-387-89520-8_2. PMID19760064.
