RESERACH SUMMARY

NKG2D is an activating immune receptor constitutively expressed in humans in most cytotoxic lymphocytes including NK and CD8+ T cells; in mice it is expressed on NK cells, but on T cells only after activation. After binding of its ligands, NKG2D activates the mechanisms that lead to lysis and cytokine secretion by immune effector cells. It thus seems reasonable that NKG2D ligands are not expressed constitutively on all cell types. Instead, their pattern of expression is affected by cell stress. In humans, NKG2D ligands (NKG2D-L) belong to two families of “stress-inducible” proteins: the polymorphic family of MHC-I related chain A/B (MICA/B) and the multi-gene family of UL16-binding proteins (ULBP, now termed RAET1A-E). The existence of such a large number of ligands for a single receptor is not fully understood, but might reflect a differential role for distinct ligands in immune surveillance or an evolutionary response to selective pressures exerted by pathogens or cancer. Our hypothesis is that the different biochemical properties of NKG2D ligands could lead them to follow distinct cellular pathways, and that these biological features would allow the cell to adapt to a variety of stress stimuli (pathogen, tumour transformation).

Interestingly, NKG2D ligands can also be shed as soluble molecules and induce a state of unresponsiveness in T and NK cells. This phenomenon is of particular importance in immune recognition of cancer, since the presence of soluble ligands for NKG2D in serum of cancer patients has been linked to poor disease prognosis.

Recent work from the laboratory, initiated at the University of Cambridge, focuses on studying the cellular and molecular differences that would explain the heterogeneity among NKG2D ligands. Our data demonstrate that release of NKG2D ligands occurs through several cellular mechanisms, including metalloprotease cleavage and release in exosomes.

Tumour release of proteins is a vehicle of communication with the immune system that can lead either to activation of the response and elimination of the tumour, or to suppression and immune escape. In the case of NKG2D ligands, the presence of soluble protein leads to inhibition of NK cell cytotoxicity, and exosomes containing NKG2D ligands are potent downmodulators of the NKG2D receptor.