Natural killer cell receptor 2B4 (CD244) intracellular signaling domain (2B4 ICD)

The Natural killer cell receptor 2B4 (CD244) intracellular signaling domain is a vital regulatory segment of the SLAM family receptors, primarily found on natural killer (NK) cells and subsets of T cells (UniProt Q9BZW8). This domain contains four immunoreceptor tyrosine-based switch motifs (ITSMs) that serve as docking sites for adapter proteins like SLAM-associated protein (SAP) and EAT-2 (PubMed: 15905547). Upon binding its ligand CD48, the 2B4 intracellular domain initiates signaling cascades that significantly enhance NK cell cytotoxicity and the production of interferon-gamma (NCBI Gene: 27221). In the absence of the SAP adapter, the domain can alternatively recruit inhibitory phosphatases, leading to immune suppression, which is a hallmark of X-linked lymphoproliferative syndrome (PubMed: 10591211). Due to its potent activating properties, the 2B4 intracellular domain is extensively utilized in synthetic biology as a costimulatory component in chimeric antigen receptors (CARs) to improve the anti-tumor efficacy and persistence of CAR-NK cell therapies (PubMed: 32661156). Its role in modulating immune responses makes it a key focus for both cancer immunotherapy and the treatment of chronic viral infections.

Other names

CD244 intracellular domain2B4 cytoplasmic tailSLAMF4 signaling domainNatural killer cell receptor 2B4p38NAIL

The 2B4 intracellular domain functions by recruiting SH2-domain containing adapter proteins, specifically SLAM-associated protein (SAP/SH2D1A), to its phosphorylated immunoreceptor tyrosine-based switch motifs (ITSMs), which subsequently activates Fyn kinase and downstream Ras/MAPK and PLC-gamma pathways to trigger NK cell degranulation and cytokine release (PubMed: 15905547).