Expression of CD137 ligand (CD137L; also known as 4-1BBL and TNFSF9) is found mainly on professional antigen-presenting cells (APCs) such as dendritic cells, monocytes/macrophages, and B cells, and its expression is upregulated during activation of these cells. However, its expression has been documented on a variety of hematopoietic cells and nonhematopoietic cells. Generally, 4-1BBL / CD137L is constitutively expressed on many types of cells but its expression levels are low except for a few types of cells. Interestingly, 4-1BBL / CD137L is coexpressed with CD137 (also known as 4-1BB and TNFRSF9) on various types of cells, but expression of CD137 / 4-1BB potently downregulates that of 4-1BBL / CD137L by cis-interactions between the two molecules resulting in endocytosis of 4-1BBL / CD137L.
4-1BB & 4-1BBL immune checkpoint pathway has been relatively well characterized in the process of inflammation, hematopoiesis, and immune tolerance. It is becoming clear that 4-1BB & 4-1BBL immune checkpoint pathway is critical in multiple steps during the progression of inflammation. In most inflammatory conditions that are caused by various stresses, early events mediated by 4-1BB & 4-1BBL immune checkpoint pathway may occur in vessels. For example, CD137 / 4-1BB on activated endothelial cells stimulates 4-1BBL / CD137L on monocytes to enhance their extravasation through activation of cell adhesion molecules. During interactions between monocytes and endothelial cells, 4-1BB & 4-1BBL bidirectional signals are delivered into endothelial cells but only 4-1BB & 4-1BBL immune checkpoint pathway takes place in monocytes. As a result, endothelial cells and monocytes secrete proinflammatory cytokines and chemokines . Once monocytes arrive at inflammatory sites, they are likely to differentiate into macrophages or dendritic cells depending upon the microenvironment of inflammatory sites. At the early phase of tissue inflammation when proinflammatory mediators become enriched in inflamed sites, 4-1BBL / CD137L signaling may elicit the differentiation of monocytes toward M1 macrophages or dendritic cells and amplify tissue inflammation. On the other hand, 4-1BB & 4-1BBL immune checkpoint pathway in parenchymal cells also can contribute to a vicious cycle of tissue inflammation. For instance, 4-1BB & 4-1BBL immune checkpoint pathway in tubular epithelial cells is a key point for exacerbating ischemia-reperfusion-induced renal inflammation by promoting recruitment of neutrophils into the kidney. These observations implicate 4-1BB & 4-1BBL immune checkpoint pathway as a convergence point to amplify tissue inflammation through recruitment of inflammatory cells and increment of proinflammatory mediator production. It remains to be clarified whether 4-1BB & 4-1BBL immune checkpoint pathway also functions as a key player after acute inflammation subsides. During the resolution phase of inflammation, however, it is likely that 4-1BB & 4-1BBL immune checkpoint pathway help tissue repair mechanisms presumably by inducing M2 macrophage differentiation and regeneration of parenchymal cells including epithelial cells. It is needed to be noted that outcomes of 4-1BB & 4-1BBL immune checkpoint pathway are context-dependent in most cases. Here, I propose that 4-1BB & 4-1BBL immune checkpoint pathway functions as a costimulatory signal during inflammation: i.e., a primary signal determines the general fate or propensity of immune responses and the secondary 4-1BB & 4-1BBL immune checkpoint pathway reinforces the primary signaling. Primary signals are transduced via pattern recognition receptors (PRR) such as Toll-like receptors (TLR), C-type lectin receptors (NLR), NOD-like receptors (NLR) and RIG-I-like receptors (RLR), and receptors for a variety of proinflammatory mediators and growth factors. During inflammation, ligands for the primary receptors include pathogen- or damage-associated molecular patterns (PAMP or DAMP), inflammatory mediators, and growth factors. They may be provided by pathogens, damaged neighbor cells, or CD137 / 4-1BB-expressing 4-1BBL / CD137L counterpart cells. Our unpublished data demonstrated that Candida albicans activates macrophages through the primary Dectin-1 or TLR2 receptor and the secondary 4-1BBL / CD137L. Fulminant inflammation occurs after infection with C. albicans only when both signals are present in macrophages, and each signal cannot compensate for the other in the production of inflammatory mediators by macrophages. This two signal model implicates 4-1BB & 4-1BBL immune checkpoint pathway as a safeguard that regulates the powerful and potentially harmful immune reaction and prevents the accidental triggering of responses against the host's own tissues.
Byungsuk Kwon et al. Is CD137 Ligand (CD137L) Signaling a Fine Tuner of Immune Responses? Immune Netw. 2015 Jun;15(3):121-124.
|Co-inhibitory immune checkpoint pathways||Co-stimulatory immune checkpoint pathways|
|PD1 & PD-L1 immune checkpoint pathway||CD40 & CD40L immune checkpoint pathway|
|CTLA-4 & CD80 (CD86) immune checkpoint pathway||OX40 & OX40L immune checkpoint pathway|
|B7-H3 / CD276 immune checkpoint pathway||HVEM & LIGHT immune checkpoint pathway|
|B7-H4 / B7S1 / B7x immune checkpoint pathway||CD28 & CD80 (CD86) immune checkpoint pathway|
|HVEM & BTLA immune checkpoint pathway||GITR & GITR Ligand immune checkpoint pathway|
|HVEM & CD160 immune checkpoint pathway||CD27 & CD70 immune checkpoint pathway|
|LAG3 / CD223 / Lymphocyte activation gene 3 immune checkpoint pathway||CD266 & CD155 immune checkpoint pathway|
|Galectin-9 & TIM-3 immune checkpoint pathway||ICOS & ICOS Ligand immune checkpoint pathway|
|Indoleamine 2,3-dioxygenase/IDO immune checkpoint pathway|
|VISTA / B7-H5 / GI24 immune checkpoint pathway|
|CEACAM1 / CD66a immune checkpoint pathway|
|SIRP alpha & CD47 immune checkpoint pathway|
|2B4 & CD48 immune checkpoint pathway|
|TIGIT & CD155 immune checkpoint pathway|