2B4 (CD244)-CD48 interactions provide a novel MHC class I-independent system for NK-cell self-tolerance in mice

SHIP Influences Signals from CD48 and MHC Class I Ligands That Regulate NK Cell Homeostasis, Effector Function, and Repertoire Formation

“…The early expression of 2B4 in developing NK cells may be necessary to achieve self-tolerance until a properly diverse Ly49 and CD94/NKG2 repertoire is acquired. Consistent with this hypothesis, McNerney et al (29) found that 2B4 promotes self tolerance by mature murine NK cells in rodents, and Sivori et al (30) showed that 2B4 inhibitory signals limits cytolysis by NK cells that have yet to acquire KIR expression. This putative function of 2B4 in developing NK cells could be particularly important in preventing inappropriate NK cytolysis in the BM compartment, because immature NK cells have been shown to acquire cytolytic mice (34), increased expression of SHIP in a subset of LN NK cells that lack KIR, but express 2B4 (35), and that 2B4 has inhibitory function in human LN NK cells (30).…”

2B4 inhibits NK-cell fratricide

“…Some studies of B6 mouse models indicate that 2B4-CD48 interactions augment NK-cell functions, [5][6][7]10 while other studies indicate that 2B4 inhibits functions. 3,4,8,12 The data here show that 2B4 can inhibit NK-cell fratricide among activated NK cells and that fratricide provides an explanation for some of these conflicting findings. We demonstrate that in the absence of 2B4, activated NK cells have defective proliferation and cytotoxicity due to fratricide and not the absence of an activation signal.…”

“…2 Murine 2B4 has been reported to have activating and inhibitory activities on NK cells. [3][4][5][6][7][8] These studies raise questions of how triggering the same 2B4 receptor on NK cells can lead to variable functional outcomes. Here we show that 2B4 can inhibit NK-NK fratricide and that fratricide can explain some of the apparent dual functions of 2B4 on murine NK cells.…”

2B4/CD48-Mediated Regulation of Lymphocyte Activation and Function

“…Further support for an inhibitory function of 2B4 has come from the observation that 2B4 accumulation at the interphase between NK cells and CD48-expressing cells correlates inversely with the ability of the NK cells to lyse the latter cells (29). The inhibitory receptor function of 2B4 is interesting per se, as it reveals an MHC-independent mechanism of NK cell inhibition (27,28,30) The human 2B4 gene encodes a transcript that is closely related to murine 2B4L (13,31) as well as a splice variant that differs in the extracellular domains (32). Several studies have demonstrated an activating role for 2B4 on human NK cells.…”