Characterization of inhibitory and stimulatory forms of the murine naturalkiller cell receptor 2B4

The receptor 2B4 belongs to the Ig superfamily and is found on the surface of all murine natural killer (NK) cells as well as T cells displaying non-M HC-restricted cytotoxicity. Previous studies have suggested that 2B4 is an activating molecule because cross-linking of this receptor results in incre ased cytotoxicity and gamma-interferon secretion as well as granule exocgto sis. However, it was recently shown that the gene for 2B4 encodes two diffe rent products that arise by alternative splicing. These gene products diffe r solely in their cytoplasmic domains. One form has a cytoplasmic tail of 1 50 amino acids (2B4L) and the other has a tail of 93 amino acids (2B4S). To determine the function of each receptor, cDNAs for 2B4S and 2B4L were tran sfected into the rat NK cell line RNK-16, Interestingly, the two forms of 2 B4 had opposing functions. 2B4S was able to mediate redirected lysis of P81 5 tumor targets, suggesting that this form represents an activating recepto r. However, 2B4L expression led to an inhibition of redirected lysis of P81 5 targets when the mAb 3.2.3 (specific for rat NKRP1) was used. In addition , 2B4L constitutively inhibits lysis of YAC-1 tumor targets. 2B4L is a tyro sine phosphoprotein, and removal of domains containing these residues abrog ates its inhibitory function. Like other inhibitory receptors, 2B4L associa tes with the tyrosine phosphatase SHP-2. Thus, 2B4L is an inhibitory recept or belonging to the Ig superfamily.