Type 1 diabetes is an autoimmune disease typically characterized by a long preclinical stage in which insulin-producing β cells in the pancreatic islets are destroyed by autoimmune T cells. In the June issue of Immunity, Lewis Lanier and colleagues use the non-obese diabetic (NOD) mouse to show that the ligand retinoic acid early inducible (RAE)-1, which is present in pre-diabetic islets, activates the receptor NKG2D, which is expressed on the surface of a subset of T cells and natural killer (NK) cells; furthermore, this interaction is essential for disease progression. When treated during the pre-diabetic stage, a non-depleting anti-NKG2D antibody completely prevented disease.
The NOD mouse is widely used as a model of human type 1 diabetes. Usually, inflammation of the islets is observed 10–20 weeks before T-cell destruction of the insulin-producing cells; this process and the time delay is not well understood. NKG2D is a costimulatory receptor expressed on activated NK cells and certain groups of T cells, and there is evidence that it might carry out surveillance against cancer and infections. The ligands of NKG2D, including RAE-1, are known to be molecules whose expression is triggered by oncological transformation and infection with viral and bacterial pathogens. Costimulatory molecules on T cells and other immune cells are crucial for the autoimmune response. Expression of RAE-1 family members is strictly regulated in normal cells, and little is expressed on healthy adult tissues. However, the authors found that RAE-1 was expressed on islet cells in NOD mice, but not in other strains such as C57BL/6 or BALB/c. Expression was also detected in the pancreases of adult immune-deficient NOD mice (which lack T cells and do not develop diabetes), indicating that RAE-1 expression is independent of ongoing autoimmune response.
To demonstrate the role of NKG2D in the progression of diabetes, the authors transferred T cells from diabetic NOD mice into immune-deficient NOD mice. Diabetes developed in all control mice, but not those treated with anti-NKG2D antibodies. The authors showed that the therapy impaired the clonal expansion and function of autoreactive T cells in the pancreas, although it did not prevent the initial activation of the T cells.
These findings are important because unlike other treatments reported in the NOD mouse this therapy is effective when administered relatively late in disease progression. Interestingly, NKG2D has been detected on T cells — isolated from the synovial tissue of rheumatoid arthritis patients — in the presence of one of its ligands, which raises the posibility that this receptor could play a detrimental role in other autoimmune diseases.
References
ORIGINAL RESEARCH PAPER
Ogasawara, K. et al. NKG2D blockade prevents autoimmune diabetes in NOD mice. Immunity 20, 757–767 (2004)
FURTHER READING
Raulet, D. Roles of the NKG2D immunoreceptor and its ligands. Nature Rev. Immunol. 3, 781–790 (2003)
Cerwenka, A. & Lanier, L. L. Natural killer cells. Nature Rev. Immunol. 1, 41–49 (2001)
Yokoyama, W. M. & Plougastel, B. F. M. Immune functions encoded by the natural killer gene complex. Nature Rev. Immunol. 3, 304–316 (2003)
Rights and permissions
About this article
Cite this article
Brazil, M. NKG2D receptor: a therapeutic target?. Nat Rev Drug Discov 3, 646 (2004). https://doi.org/10.1038/nrd1475
Issue Date:
DOI: https://doi.org/10.1038/nrd1475