Editors' ChoiceImmunology

Coupling NKG2D to Innate and Adaptive Immune Responses

Science's STKE  10 Dec 2002:
Vol. 2002, Issue 162, pp. tw464-TW464
DOI: 10.1126/stke.2002.162.tw464

Two reports this week help explain the versatility of the receptor known as NKG2D, which functions on natural killer (NK) cells, macrophages, and CD8+ T cells in the immune system and provides part of the mechanism by which tumor cells can be removed from the body. The receptor recognizes ligands specifically expressed on the surface of cells that have experienced infection, transformation, or other stress. In the adaptive immune response, NKG2D does not activate T cells on its own but provides a costimulatory signal that enhances activation through the T cell receptor. However, in innate immune responses, NKG2D functions on its own to fully activate NK cells. Defenbach et al. and Gilfillan et al. show that the distinct signaling roles are produced by the association of NKG2D with two different signaling subunits--known as DAP10 and DAP12--and that alternative splicing of NKG2D modulates its association with these subunits. CD8+ T cells express only DAP10, which links NKG2S only to costimulatory signals, and T cells from animals lacking DAP10 showed no response to tumor antigens. NK cells express both DAP10 and DAP12, and the latter was found to couple the NKG2D receptor to fully stimulatory signals. In fact, full activation could be conferred on NKG2D in T cells by expression of DAP12 in those cells. When freshly isolated, so-called "naïve" NK cells expressed only the long form of NKG2D, which binds only DAP10. Upon stimulation, the NK cells made the short form of NKG2D, which coupled to DAP12 and enabled direct activation through the receptor. A News and Views item by Long helps put all the pieces together.

S. Gilfillan, E. L. Ho, M. Cella, W. M. Yokoyama, M. Colonna, NKG2D recruits two distinct adapters to trigger NK cell activation and costimulation. Nat. Immunol. 3, 1150-1155 (2002). [Online Journal]

A. Diefenbach, E. Tomasello, M. Lucas, A. M. Jamieson, J. K. Hsia, E. Vivier, D. H. Raulet, Selective associations with signaling proteins determine stimulatory versus costimulatory activity of NKG2D. Nat. Immunol. 3, 1142-1149 (2002). [Online Journal]

E. O. Long, Versatile signaling through NKG2D. Nat. Immunol. 3, 1119-1120 (2002). [Online Journal]