Research ArticleImmunology

A nanoscale reorganization of the IL-15 receptor is triggered by NKG2D in a ligand-dependent manner

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Science Signaling  10 Apr 2018:
Vol. 11, Issue 525, eaal3606
DOI: 10.1126/scisignal.aal3606

Distinct effects on NK cells

Natural killer (NK) cells perform immune surveillance for virally infected cells and tumor cells. The balance between the engagement of activating receptors, such as NKG2D, and inhibitory receptors on the NK cell surface determines whether the cells kill their targets. Through superresolution microscopy, Bálint et al. showed that NKG2D on the surface of unstimulated NK cells was organized into nanoclusters, which became differentially reorganized depending on whether the cells were exposed to MICA or ULBP2, two NKG2D ligands found on tumor cells. Stimulation with ULBP2, but not MICA, caused NKG2D to cluster with the receptor for the cytokine IL-15, which can also be presented on tumor cells, synergizing with NKG2D to enhance NK cell responses. These data suggest that NKG2D ligands have distinct outcomes on NK cell function, which may have relevance in the use of NK cells as an immunotherapy.


Natural killer group 2D (NKG2D), an activating receptor on natural killer (NK) cells and a subset of T cells, recognizes stress-inducible proteins, including MICA and ULBP2, which are present on infected or transformed cells. Whether each NKG2D ligand (NKG2DL) has a distinct biological role is not clear. Using superresolution microscopy, we found that NKG2D is constitutively arranged in nanoclusters at the surface of human primary NK cells. Nanoclusters of NKG2D became smaller upon ligation with MICA but became larger upon activation by ULBP2. In addition, ULBP2 induced the reorganization of nanoclusters of the cytokine receptor subunit for both interleukin-2 (IL-2) and IL-15 (IL-2/IL-15Rβ), such that these cytokine receptor subunits coalesced with nanoclusters of NKG2D. Functionally, the response of NK cells activated by ULBP2 was augmented by an interaction between ULBP2-bound NKG2D and IL-15R ligated by IL-15 (trans-presented by IL-15Rα–coated surfaces). These data suggest that NKG2DLs are not equivalent in their capacity to activate NKG2D and establish a previously unknown paradigm in how ligand-induced changes to the nanoscale organization of the cell surface can affect immune responses.

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