NK Cell Proliferation Induced by IL-15 Transpresentation Is Negatively Regulated by Inhibitory Receptors

Abstract

IL-15 bound to the IL-15 receptor α chain (IL-15Rα) is presented in trans to cells bearing the IL-2 receptor β and γc chains. 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 down-regulation 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. Co-engagement 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.

Independent control of natural killer cell responsiveness and homeostasis at steady-state by CD11c+ dendritic cells

“…With regard to these early molecular events, we noted that the steady-state phosphorylation of a third major signaling protein, S6, was not altered upon DC deletion. This finding might be related to recently identified IL-15-independent pathway for S6 phosporylation29. Our in vitro findings of a link between NKG2D expression and IL-15 treatment, coupled to previously published data in the same direction by others26303132, lead us to favour a early IL-15 withdrawal as an explanation for reduced NKG2D expression.…”

Dendritic Cell–Derived IL-32α: A Novel Inhibitory Cytokine of NK Cell Function

“…2). Our findings complement another recent study showing that IL-15-induced NK cell proliferation is negatively regulated by inhibitory receptors (53). Indeed, the control of NK cell activation and inhibition by and following IL-15 is critical.…”

Impaired NK-mediated regulation of T-cell activity in multiple sclerosis is reconstituted by IL-2 receptor modulation

“…We could demonstrate that DAC HYP-mediated increased activation of NK cells depends on the presence of DCs. DCs have been shown to cross-present IL-2 and IL-15 to lymphocytes via the IL-2Rα (64) and IL-15Rα chain (57,65,66), respectively. Both cytokines are transpresented to and signal through the IL-2Rβ and common γ-chain, and blocking IL-2Rα cross-presentation using DAC HYP might therefore result in enhanced IL-15 signaling in NK cells, leading to the increased cytolytic activity.…”