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. 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 
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).
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.
^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 Immunology149 (12): 3817–26. PMID1281189.
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 Research11 (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 Science11 (4): 426–38. doi:10.1159/000077892. PMID15153777.