CD40 & CD40L Immune Checkpoint Pathway

CD40 & CD40L Immune Checkpoint Pathway: Description

CD40 / TNFRSF5 is a member of the tumor necrosis factor (TNF) superfamily and is highly expressed on nearly all B-cell malignancies. It is well established that interaction of CD40 / TNFRSF5 with its natural ligand CD40L / CD154 / TNFSF5 can rescue tumor cells from apoptosis, prolong survival and augment proliferation. CD40L / CD154 / TNFSF5 is provided either by the microenvironment, i.e. infiltrating T-cells, dendritic cells and mast cells, and/or by the tumor itself, i.e. coexpression of CD40 / TNFRSF5 and CD40L / CD154 / TNFSF5 on lymphoma cells as well as secretion of biologically active, soluble CD40L / CD154 / TNFSF5.
Numerous studies have indicated that CD40 & CD40L immune checkpoint pathway is a major regulating factor of immune responses. Briefly, CD40 & CD40L immune checkpoint pathway affects the immune system in the following four ways (5): (1) CD40 & CD40L immune checkpoint pathway "activates" or "matures" antigen-presenting cells (APCs, mainly macrophages and dendritic cells) to express co-stimulatory molecules including B7 (CD80 and CD86, both ligands for CD28), ICAM-1 (CD54), and CD44. These co-stimulatory signals are needed for T cells to become fully activated, rather than anergic, after T cell receptor (TCR)-stimulation. (2) CD40 & CD40L immune checkpoint pathway induces macrophages and dendritic cells to make interleukin-12 (IL-12), IL-18, and other cytokines. In an immunological response, CD40L / CD154 / TNFSF5 is the primary stimulus for IL-12 production (in the absence of microbial invasion). IL-12 and IL-18 stimulate NK cells for interferon-γ (IFN-γ) production. IL-12 causes CD4+ T cells to differentiate into type 1 helper T cells (Th1) that mediate delayed-type hypersensitivity responses. (3) CD40L / CD154 / TNFSF5-expressing CD4+ T cells are generally required for the generation of cytotoxic T lymphocytes (CTLs) against tumors and virus-infected cells. As in CD4+ T cell activation, CD40 & CD40L immune checkpoint pathway activates APCs to express the co-stimulatory molecules needed to fully activate ("cross-prime") CTLs already responding to antigen/MHC class I complexes. (4) CD40 & CD40L immune checkpoint pathway promotes the differentiation of activated B cells and, with few exceptions, is required for the "class switch" from IgM to IgG production.

CD40 & CD40L Immune Checkpoint Pathway: Reference

Richard S. Kornbluth et al. The emerging role of CD40 ligand in HIV infection. Journal of Leukocyte Biology. 2000 ; 68:373-382.