CD154, also calledCD40 ligand orCD40L, is aprotein that is primarily expressed on activatedT cells[5] and is a member of theTNF superfamily of molecules. It binds toCD40 onantigen-presenting cells (APC), which leads to many effects depending on the target cell type. In total CD40L has three binding partners: CD40,α5β1 integrin andintegrin αIIbβ3. CD154 acts as a costimulatory molecule and is particularly important on a subset ofT cells calledT follicular helper cells (TFH cells).[6] On TFH cells, CD154 promotesB cell maturation and function by engaging CD40 on the B cell surface and therefore facilitating cell-cell communication.[7] A defect in this gene results in an inability to undergoimmunoglobulin class switching and is associated withhyper IgM syndrome.[8] Absence of CD154 also stops the formation ofgerminal centers and therefore prohibiting antibodyaffinity maturation, an important process in theadaptive immune system.
In 1991, three groups reported discovering CD154.Seth Lederman, Michael Yellin, and Leonard Chess atColumbia 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.[9] Richard Armitage atImmunex cloned a cDNA encoding CD154 by screening an expression library with CD40-Ig.[10] Randolph Noelle atDartmouth Medical School generated an antibody that bound a 39 kDa protein on murine T cells and inhibited helper function.[11] Noelle contested Lederman's patent, but the challenge (called an interference) was rejected on all counts[12]
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).[13]
CD40L plays a central role in costimulation and regulation of the immune response viaT cell priming and activation of CD40-expressing immune cells.[14] At least 46 disease-causing mutations in this gene have been discovered.[15]
In themacrophage, the primary signal for activation isIFN-γ from Th1 typeCD4T cells. The secondary signal is CD40L on the T cell, which bindsCD40 on themacrophage cell surface. As a result, the macrophage expresses more CD40 andTNF receptors on its surface, which helps increase the level of activation. The activated macrophage can then destroyphagocytosed bacteria and produce more cytokines.
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 presentantigens to a specialized group ofhelper T cells calledTFH cells. If an activatedTFH 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.[16] The T cell also producesIL-4, which directly influences B cells. As a result of this stimulation, the B cell can undergo rapid cellular division to form agerminal center whereantibodyisotype switching andaffinity maturation occurs, as well as their differentiation toplasma cells andmemory 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 littleclass switching orgerminal centre formation, and immune responses are severely inhibited.[17]
^Lederman S, Yellin MJ, Cleary AM, Pernis A, Inghirami G, Cohn LE, et al. (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):2163–2171.doi:10.4049/jimmunol.152.5.2163.PMID7907632.S2CID42460521.
^"Patent 5,474,771"(PDF).UNITED STATES PATENT AND TRADEMARK OFFICE. U.S. Patent Office. Archived fromthe original(PDF) on 2016-03-04. Retrieved2016-06-18.
^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):3329–3337.doi:10.4049/jimmunol.155.7.3329.PMID7561026.S2CID39514335.
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.PMID8907262.
Bhushan A, Covey LR (2002). "CD40:CD40L interactions in X-linked and non-X-linked hyper-IgM syndromes".Immunologic Research.24 (3):311–324.doi:10.1385/IR:24:3:311.PMID11817328.S2CID19537892.
Cheng G, Schoenberger SP (2002). "CD40 signaling and autoimmunity".Signal Transduction Pathways in Autoimmunity. Current Directions in Autoimmunity. Vol. 5. pp. 51–61.doi:10.1159/000060547.ISBN3-8055-7308-1.PMID11826760.
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.
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. Vol. 647. pp. 8–36.doi:10.1007/978-0-387-89520-8_2.ISBN978-0-387-89519-2.PMID19760064.
