The role of 2B4-mediated inhibition in murine natural killer cell self-tolerance.

摘要

The 2B4 (CD244) receptor is expressed by all NK cells, as well as a subset of memory CD8+ ab T cells, gd T cells, basophils and monocytes. The ligand to 2B4, CD48, is expressed on all nucleated hematopoetic cells. Upon ligation to CD48, murine 2B4 has been reported to have activating and inhibitory functions on NK cells. Here I provide evidence to support a novel explanation of the apparent dual function of 2B4 on murine NK cells. My data suggests that 2B4 only appears to augment murine IL-2 activated NK, or lymphokine activated killer (LAK) cell cytotoxicity and proliferation because in the absence of 2B4-mediated inhibition, NK LAK cells undergo fratricide. Thus, in the absence of 2B4-mediated inhibition, NK LAK cell populations are less functional because there are less cells, and not because there is a lack of an activating signal. I found that 2B4 not only protects NK LAK cells from killing each other, but also activated T cells, in vitro. Furthermore, we showed that 2B4 inhibits NK cells from killing NK and T cells that are activated in vivo. Thus, for the first time, we have shown in various model systems that in the absence of a non-MHC binding NK inhibitory receptor, activated NK cells can reject healthy and normal, activated NK and T cells. Overall, this work shows that unlike "classical" MHC class I mediated NK self-tolerance, 2B4-mediated inhibition is only required for activated NK self-tolerance.