After completion of several of our objectives in FY12, this project has taken a new direction. We are defining the minimal requirements for the activation of NK cell proliferation, using approaches that have been successful in previous projects. The interleukin 15 (IL-15) is essential for NK cell survival and proliferation. Unlike other cytokines, which are soluble, IL-15 is bound to the alpha chain of the IL-15 receptor (IL-15R). The IL-15Ralpha-IL-15 complex is not expressed on NK cells but on other cells, which trans-present IL-15 to the beta and gamma chains of the IL-15R expressed on NK cells. The IL-15Rbetagamma complex then transmits signals to the NK cell for survival, proliferation, and transcription of a specific set of genes. Trans-presentation of IL-15 in the context of an immunological synapse opens the possibility that signaling for NK cell proliferation may be subject to regulation by other receptor-ligand interactions. Using insect cells transfected with IL-15Ralpha, either alone or in combination with ligands for other NK receptors, we have shown that IL-15 trans-presentation occurs independently of adhesion through integrin, and of signaling by other activation receptors.

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Long, Eric O; Kim, Hun Sik; Liu, Dongfang et al. (2013) Controlling natural killer cell responses: integration of signals for activation and inhibition. Annu Rev Immunol 31:227-58
Liu, Dongfang; Bryceson, Yenan T; Meckel, Tobias et al. (2009) Integrin-dependent organization and bidirectional vesicular traffic at cytotoxic immune synapses. Immunity 31:99-109
Bryceson, Yenan T; Ljunggren, Hans-Gustaf; Long, Eric O (2009) Minimal requirement for induction of natural cytotoxicity and intersection of activation signals by inhibitory receptors. Blood 114:2657-66
Bryceson, Yenan T; Long, Eric O (2008) Line of attack: NK cell specificity and integration of signals. Curr Opin Immunol 20:344-52
Schleinitz, Nicolas; March, Michael E; Long, Eric O (2008) Recruitment of activation receptors at inhibitory NK cell immune synapses. PLoS One 3:e3278