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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Romera-Cárdenas, Gema; Thomas, L Michael; Lopez-Cobo, Sheila et al. (2016) Ionomycin Treatment Renders NK Cells Hyporesponsive. PLoS One 11:e0150998
Mitra, Suman; Ring, Aaron M; Amarnath, Shoba et al. (2015) Interleukin-2 activity can be fine tuned with engineered receptor signaling clamps. Immunity 42:826-38
Rajagopalan, Sumati; Long, Eric O (2013) Found: a cellular activating ligand for NKp44. Blood 122:2921-2
Ombrello, Michael J; Remmers, Elaine F; Sun, Guangping et al. (2012) Cold urticaria, immunodeficiency, and autoimmunity related to PLCG2 deletions. N Engl J Med 366:330-8
Kim, Hun Sik; Long, Eric O (2012) Complementary phosphorylation sites in the adaptor protein SLP-76 promote synergistic activation of natural killer cells. Sci Signal 5:ra49
Martinez, Emily; Brzostowski, Joseph A; Long, Eric O et al. (2011) Cutting edge: NKG2D-dependent cytotoxicity is controlled by ligand distribution in the target cell membrane. J Immunol 186:5538-42
Liu, Dongfang; Martina, Jose A; Wu, Xufeng S et al. (2011) Two modes of lytic granule fusion during degranulation by natural killer cells. Immunol Cell Biol 89:728-38
Agüera-González, Sonia; Gross, Catharina C; Fernández-Messina, Lola et al. (2011) Palmitoylation of MICA, a ligand for NKG2D, mediates its recruitment to membrane microdomains and promotes its shedding. Eur J Immunol 41:3667-76
Dustin, Michael L; Long, Eric O (2010) Cytotoxic immunological synapses. Immunol Rev 235:24-34
Liu, Dongfang; Meckel, Tobias; Long, Eric O (2010) Distinct role of rab27a in granule movement at the plasma membrane and in the cytosol of NK cells. PLoS One 5:e12870

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