NKG2D: A versatile player in the immune system

- NKG2D can induce direct killing of target cells expressing its ligands, which are stress-induced.
- NKG2D is expressed in hematopoietic precursors and affects NK cell and B1a cell development.
- NKG2D deficiency results in permanent hyper-reactivity of NK cells and hypo-responsiveness of B1a cells.
- On CD8 T cells, NKG2D mediates effector cell differentiation and memory formation during priming.
- The role of NKG2D in a given subset depends on the adaptors Dap10 and Dap12 and the presence of unknown co-factors.

NKG2D is known as a potent activating receptor of the immune system. It is expressed on a multitude of immune cells, including NK cells and different subsets of T cells. NKG2D recognizes various MHC I-like ligands that are induced on target cells exposed to stressors such as viral infection, DNA damage and oncological transformation. NKG2D drives or facilitates cytotoxic and cytokine responses towards cells expressing its ligands to eliminate the threat. Therefore, NKG2D is usually classified as a sensor that translates cellular stress into activation signals for immune cells. However, more recently it has become evident that NKG2D plays a role beyond direct killing of target cells. Lack of NKG2D affects development of NK cells in the bone marrow, resulting in hyperreactive NK cells. NKG2D deficiency on CD8 T cells affects the ability of effector cells to produce cytokines in response to T cell receptor engagement and reduces their capacity to establish immunological memory. Although NKG2D is not expressed on B cells subsets, lack of this receptor in hematopoietic precursors affects B cell development. Homing of mature B2 cells is altered in NKG2D-deficient mice and they have a strong reduction in peripheral B1a cell numbers, resulting in increased susceptibility to bacterial infections. The exact molecular mechanisms via which NKG2D mediates these versatile functions is still being explored, but appears to depend on the control of activation thresholds, either in hematopoietic precursors or mature immune cell subsets. In this review, we will elaborate on the underappreciated developmental and regulatory roles of NKG2D.