2B4 Immune Checkpoint Molecule for Drug Development
Overview of 2B4
2B4, also named SLAMF4/CD244, was first described on natural killer cells (NK) cells as a stimulatory receptor that initiates cytokine release and cytolytic activity. Subsequently, it was also described on monocytes, basophils, Eos, γδ T cells, and on a subpopulation of CD8+ T cells. Like most signaling lymphocytic activation molecule (SLAM) family members, the 2B4 extracellular region comprises one IgV and one IgC domain. In contrast, unlike most of them, its intracellular part is composed of four ITSMs.
The 2B4 belongs to the CD2 subset of the Ig superfamily due to homology in their extracellular domains. 2B4 contains one membrane distal Ig V-like domain and an Ig-C2-like domain.
Expression of 2B4
2B4, which bears four ITSM motifs, is expressed by all NK cells, a subset of memory-phenotype CD8+ αβ T cells, γδ T cells, basophils, and monocytes. 2B4 is also expressed on murine dendritic cells (DC), mast cells (MCs), and weakly on macrophages.
Function of 2B4
Since the initial discovery of 2B4, there has been increasing evidence that 2B4 also has inhibitory potential. 2B4 appears to be inhibitory in the absence of functional SLAM-associated protein (SAP), as seen in X-linked lymphoproliferative disease (XLP) patients and normal developing human NK cells. When the murine 2B4 isoforms were individually transfected into an NK cell line, the long-form 2B4 inhibited NK cytotoxicity. Now, results from experiments employing 2B4-deficient mice underscore the inhibitory role for murine 2B4.
Pathway of 2B4
An important question regarding 2B4 is the transformation of intracellular tyrosine-based switch motifs (ITSM) containing receptor signals. Upon ligation, the ITSM motifs of 2B4 are phosphorylated by the Src family kinases Fyn and Lck. Subsequently, 2B4 has been shown to interact with several SH2 domain-containing proteins, SHP-1, -2, SAP, and EAT-2. This is the point at which the activating and inhibitory pathways diverge. In the activating pathway, SAP appears to function by recruiting other signaling molecules, specifically Fyn. Fyn may amplify the activating signal in part by further phosphorylating 2B4. 2B4 also activates linkers for activation of T cells (LAT) and Vav-1, leading to PI3K activation, map kinase activation, and calcium flux, culminating in activation of lysis and cytokine production. This pathway best fits for activating signals from human 2B4 upon interaction with a target cell.
Fig.1 Models of 2B4 activating and inhibitory signaling. (McNerney, 2005)
2B4 in Diseases
Decreased expression of 2B4 on NK cells was described in multiple myeloma (MM) patients and on platelets, monocytes, and NK cells in systemic lupus erythematosus. On the contrary, in human immunodeficiency virus-positive patients, CD4+ invariant natural killer T (iNKT) cells highly express 2B4. In this case, 2B4 expression negatively correlates with INF-γ secretion from these cells. Remarkably, 2B4 is also highly expressed on CD4+ T cells in septic patients. Blockade of 2B4 by anti-2B4 mAb results in an increased survival rate in the cecal ligation and puncture mouse model, thus indicating that this receptor might be an attractive pharmacological target in this situation. A potential role of 2B4 as a possible therapeutic target in some diseases, depending on its expression and function, has emerged from all these studies.
Services at Creative Biolabs
Creative Biolabs is a professional immune checkpoint drug development service provider. We are now capable of providing a series of 2B4 immune checkpoint drug development services, including but not limited to: