Antón Hurtado, Olga MaríaVielkind, SusinaPeterson, MaryTagaya, YutakaLong, Eric2024-01-312024-01-312015Olga M. Anton, Susina Vielkind, Mary E. Peterson, Yutaka Tagaya, Eric O. Long; NK Cell Proliferation Induced by IL-15 Transpresentation Is Negatively Regulated by Inhibitory Receptors. J Immunol 15 November 2015; 195 (10): 4810–4821. https://doi.org/10.4049/jimmunol.15004140022-176710.4049/jimmunol.1500414https://hdl.handle.net/20.500.14352/97015IL-15 bound to the IL-15Rα–chain (IL-15Rα) is presented in trans to cells bearing the IL-2Rβ–chain and common γ-chain. As IL-15 transpresentation occurs in the context of cell-to-cell contacts, it has the potential for regulation by and of other receptor–ligand interactions. In this study, human NK cells were tested for the sensitivity of IL-15 transpresentation to inhibitory receptors. Human cells expressing HLA class I ligands for inhibitory receptors KIR2DL1, KIR2DL2/3, or CD94-NKG2A were transfected with IL-15Rα. Proliferation of primary NK cells in response to transpresented IL-15 was reduced by engagement of either KIR2DL1 or KIR2DL2/3 by cognate HLA-C ligands. Inhibitory KIR–HLA-C interactions did not reduce the proliferation induced by soluble IL-15. Therefore, transpresentation of IL-15 is subject to downregulation by MHC class I–specific inhibitory receptors. Similarly, proliferation of the NKG2A+ cell line NKL induced by IL-15 transpresentation was inhibited by HLA-E. Coengagement of inhibitory receptors, either KIR2DL1 or CD94-NKG2A, did not inhibit phosphorylation of Stat5 but inhibited selectively phosphorylation of Akt and S6 ribosomal protein. IL-15Rα was not excluded from, but was evenly distributed across, inhibitory synapses. These findings demonstrate a novel mechanism to attenuate IL-15–dependent NK cell proliferation and suggest that inhibitory NK cell receptors contribute to NK cell homeostasis.engjournal article1550-6606https://doi.org/10.4049/jimmunol.1500414open accessBiología molecular (Biología)24 Ciencias de la Vida