Regulation of the NKG2D ligand Mult1 by shedding (48.22)

Abstract Natural Killer group 2D (NKG2D) is an activating receptor expressed by NK cells and some T cells that recognizes a diverse family of ligands, including the Rae-1 family, H60, and Mult1 in the mouse, and the MICA and ULBP families in humans. The binding of NKG2D to its ligands plays an important role in immunosurveillance of tumors and infectious pathogens, but disregulation of this system has been tied to autoimmunity and chronic inflammatory disease. Intriguingly, some of human NKG2D ligands such as MICA and MICB can be shed from tumor cells and have been detected in sera from patients with various types of cancer. Here we report that the mouse NKG2D ligand Mult1 protein is shed from the surface of cells and that the resulting soluble Mult1 can still bind to NKG2D. While cell-bound Mult1 causes downregulation of surface NKG2D, soluble Mult1 did not alter NKG2D expression on NK cells in vitro. Furthermore, shedding of Mult1 could be blocked by the general matrix metalloproteinase (MMP) inhibitor BB94. Finally, soluble Mult1 is elevated in the sera from Eu-Myc transgenic mice, a strain that develops B lymphomas. This study represents the first instance of NKG2D ligand shedding in the mouse, which provides an important animal model to probe the mechanisms underlying shedding and its impact on immune recognition.