2B4/CD244 Signaling in Immune Regulation and Its Role in Infection, Cancer, and Immune Tolerance

2B4 (CD244), the fourth member of the signaling lymphocyte activation molecule (SLAM) family, is expressed by virtually all human and murine hematopoietic lineages and functions as a context-dependent activating or inhibitory receptor. This review provides a comprehensive update on the gene organization, molecular architecture, glycosylation patterns, and alternatively spliced isoforms of 2B4, highlighting how these structural variables dictate ligand (CD48) affinity and downstream signaling outcome. The roles of 2B4 in natural killer (NK) cells, CD8⁺ T cells, dendritic cells, myeloid-derived suppressor cells, B cells, eosinophils, and basophils were then systematically demonstrated, emphasizing their dual capacity to either potentiate cytotoxicity and cytokine production or enforce immune tolerance and exhaustion. Mechanistically, the balance between SLAM-associated protein (SAP)-mediated activation and SHP-1/2/SHIP-driven inhibition emerges as a central rheostat that is dynamically tuned by SAP availability, and the microenvironment. Clinically, exaggerated 2B4 signaling is associated with viral persistence in MCMV, HCV, HIV, and SARS-CoV-2 infections, promotes tumor immune escape in melanoma, multiple myeloma, and head-and-neck cancer, and compromises maternal-fetal tolerance, whereas insufficient signaling weakens antimicrobial immunity. Parallel pre-clinical studies validate 2B4 blockade as a rational combinatorial strategy to reinvigorate exhausted CD8⁺ T and NK cells, while soluble CD48 emerges as a dynamic biomarker of disease activity. Collectively, these insights redefine 2B4 as a systems-level integrator of immune homeostasis and a tractable precision-immunotherapy node whose therapeutic manipulation can rebalance immunity across infection, cancer, and pregnancy.