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J Immunol. 2014 Sep 15;193(6):2764-2771. doi: 10.4049/jimmunol.1400920. Epub 2014 Aug 4.

A truncated human NKG2D splice isoform negatively regulates NKG2D-mediated function.

Author information

Department of Veterinary & Animal Sciences/Immunology, University of Massachusetts, Amherst, MA.
Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.
Department of Immunology, University of Toronto, Toronto, Canada.
Department of Pediatrics, Stanford University School of Medicine, Stanford, CA.
Contributed equally


Natural killer group 2, member D (NKG2D) is a stimulatory receptor expressed by NK cells and a subset of T cells. NKG2D is crucial in diverse aspects of innate and adaptive immune functions. In this study, we characterize a novel splice variant of human NKG2D that encodes a truncated receptor lacking the ligand-binding ectodomain. This truncated NKG2D (NKG2D(TR)) isoform was detected in primary human NK and CD8(+) T cells. Overexpression of NKG2D(TR) severely attenuated cell killing and IFN-γ release mediated by full-length NKG2D (NKG2D(FL)). In contrast, specific knockdown of endogenously expressed NKG2D(TR) enhanced NKG2D-mediated cytotoxicity, suggesting that NKG2D(TR) is a negative regulator of NKG2D(FL). Biochemical studies demonstrated that NKG2D(TR) was bound to DNAX-activated protein of 10 kDa (DAP10) and interfered with the interaction of DAP10 with NKG2D(FL). In addition, NKG2D(TR) associated with NKG2D(FL), which led to forced intracellular retention, resulting in decreased surface NKG2D expression. Taken together, these data suggest that competitive interference of NKG2D/DAP10 complexes by NKG2D(TR) constitutes a novel mechanism for regulation of NKG2D-mediated function in human CD8(+) T cells and NK cells.

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