NKG2D is an activating receptor that is expressed by T cells, as well as by natural killer (NK) cells and macrophages. Previously, it had been found to associate with the adaptor molecule DAP10. When engaged on T cells, NKG2D transmits a co-stimulatory signal, but on NK cells, it can provide a direct stimulatory signal. How can a single receptor transmit such different signals in different cell types? The molecular basis for this ability of NKG2D is now shown in two papers published in the December issue of Nature Immunology.
Diefenbach and colleagues identified two splice variants of mouse NKG2D — a long form (NKG2D-L) that has a 13-amino-acid extension at the amino terminus, and a short form (NKG2D-S). Resting NK cells express messenger RNA encoding NKG2D-L, and after activation, mRNA encoding NKG2D-S is upregulated. Neither isoform can be detected in resting macrophages or CD8+ T cells. After T-cell receptor stimulation, the expression of both isoforms is upregulated on CD8+ T cells, whereas stimulation of macrophages with bacterial lipopolysaccharide upregulates the expression of NKG2D-S preferentially. Immunoprecipitation studies showed that the two isoforms associate differentially with the adaptor molecules DAP10 and DAP12 (also known as KARAP) — NKG2D-L associates only with DAP10, whereas NKG2D-S can associate with both DAP10 and DAP12. Because CD8+ T cells do not express DAP12, the two NKG2D isoforms that are expressed by activated T cells can interact only with DAP10, whereas activated NK cells can transmit signals through DAP10 and DAP12. Could the failure of T cells to respond directly to signals through NKG2D in the absence of co-stimulation be due to the absence of DAP12 in these cells? Ectopic expression of DAP12 in CD8+ T cells allowed a direct stimulatory signal to be transmitted through NKG2D-S. NK cells from Dap12−/− mice have defective signalling through NKG2D, which would not have been predicted from previous results.
Gilfillan and colleagues generated Dap10−/− mice to investigate the function of this adaptor. Although DAP10 was known previously to associate only with NKG2D, expression studies showed that the expression of NKG2D is low, but detectable, on NK cells, but absent on T cells. Activation of NK cells resulted in the upregulation of expression of NKG2D, but this did not occur when T cells were activated. How can NKG2D be expressed by NK cells in the absence of DAP10? The obvious explanation is that NKG2D can associate with another adaptor molecule, possibly DAP12. Immunoprecipitation studies showed that this is indeed the case.
These studies indicate that the differential signalling ability of NKG2D depends both on the cell type and the activation state, which is determined by the differential expression of DAP10 versus DAP12, and on the two different NKG2D isoforms. It makes sense that NKG2D can deliver a direct stimulatory signal to NK cells, but only a co-stimulatory signal to T cells, because the specificity of T-cell signalling would be compromised by direct stimulation of T cells by NKG2D.
ORIGINAL RESEARCH PAPERS
Diefenbach, A. et al. Selective associations with signaling proteins determine stimulatory versus costimulatory activity of NKG2D. Nature Immunol. 3, 1142–1149 (2002)
Gilfillan, S., Lo, E. L., Cella, M., Yokoyama, W. M. & Colonna, M. NKG2D recruits two distinct adapters to trigger NK-cell activation and costimulation. Nature Immunol. 3, 1150–1155 (2002)
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Bell, E. Dual role for NKG2D. Nat Rev Immunol 3, 4 (2003). https://doi.org/10.1038/nri988
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DOI: https://doi.org/10.1038/nri988
