RESEARCH HIGHLIGHTS

Nature Reviews Immunology | AOP, published online 7 April 2014; doi:10.1038/nri3664

NPG

NATURAL KILLER CELLS A TACTILE restraint

The immunoglobulin super­family of interferon-γ (IFNγ) and in the in Cd226–/– mice. Confirming the member CD96 (also known as proportion of IFNγ+ splenic NK cells. direct effect of the CD155–CD96 TACTILE) negatively controls Wild-type and Cd96–/– mice survived interaction on NK cells, the produc- cytokine production by natural killer equally well when they were depleted tion of IFNγ by wild-type NK cells (NK) cells, according to the first of NK cells before LPS injection, and in response to interleukin‑12 (IL‑12) in vivo functional study of this recep- Cd96–/– NK cells that were transferred and IL‑18 was decreased in the pres- tor. Mark Smyth and colleagues show into immunodeficient recipient mice ence of plate-bound CD155, and this that this function of CD96 is relevant before LPS challenge produced more effect could be reversed by a blocking to the NK cell-induced pathology of IFNγ compared with transferred antibody specific for CD96. (LPS)-induced wild-type NK cells, which shows that The counterbalancing effects of endotoxicosis, as well as to NK cell- the function of CD96 in this model is activating CD226 and inhibitory mediated regulation of tumour NK cell intrinsic. CD96 are also relevant to NK cell- formation and metastasis. There was marked induction mediated antitumour immunity. CD96, together with CD226 of CD155 expression on dendritic Cd226–/– mice had more lung and TIGIT, belongs to a family of cells (DCs) and after metastases than wild-type mice fol- receptors that interact with nectin LPS injection, and Cd96–/– NK cells lowing injection of a melanoma cell and nectin-like ligands. CD226 produced more IFNγ than wild- line, whereas immunodeficient mice and TIGIT have a common ligand, type NK cells when cultured with reconstituted with Cd96–/– NK cells CD155 (also known as NECL5 CD155+ bone marrow-derived DCs had fewer metastases than the and poliovirus receptor), and they and LPS. These results indicate that mice reconstituted with wild-type reportedly counterbalance each CD96 inhibits IFNγ production NK cells. This host-protective effect other in terms of their regulation by NK cells in response to CD155 of CD96 deficiency was dependent of NK cell function; CD226 activates induction by LPS. Whereas there on IFNγ production by NK cells. NK cell-mediated cytotoxicity, was no effect of the absence of Similarly, Cd96–/– mice were more whereas TIGIT is an inhibitory TIGIT on the response to LPS, resistant than wild-type mice to NK cell receptor. By contrast, little is Cd226–/– mice had a decreased chemically induced fibrosarcoma, known about the function of CD96, frequency of IFNγ+ NK cells, which in an IFNγ- and NK cell-dependent CD96 which is also expressed by NK cells indicates that CD226 and CD96 manner. Further studies of human inhibits IFN and can also bind CD155. have opposing roles in the regulation NK cells will be required to determine γ The authors generated Cd96–/– of NK cells in this model. the therapeutic potential of targeting production mice and showed that the numbers Although CD226 and CD96 CD96 to promote NK cell activity in by NK cells and phenotypes of the main immune can compete for binding to CD155 the context of cancer. in response cell subsets were normal. Following in vitro, the inhibitory function of Kirsty Minton sub-maximal LPS challenge, Cd96–/– CD96 in vivo was not a result of com- to CD155 ORIGINAL RESEARCH PAPER Chan, C. J. et al. mice had significantly decreased petitive depletion of CD155 from the The receptors CD96 and CD226 oppose each induction by survival compared with wild-type activating receptor CD226, as shown other in the regulation of mice, and this was associated with by the ability of CD96 deficiency functions. Nature Immunol. http://dx.doi.org/ LPS 10.1038/ni.2850 (2014) marked increases in the serum level to increase the production of IFNγ

NATURE REVIEWS | IMMUNOLOGY VOLUME 14 | MAY 2014

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