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

IL-15 bound to the IL-15Rα-chain (IL-15Rα) is presented in trans to cells bearing the IL-2Rß-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.

Integrin regulation by RhoA in thymocytes.

The guanine nucleotide-binding protein Rho has essential functions in T cell development and is important for the survival and proliferation of T cell progenitors in the thymus. To explore the mechanisms used by RhoA to control thymocyte biology, the role of this GTPase in the regulation of integrin-mediated cell adhesion was examined. The data show that RhoA activation is sufficient to stimulate beta(1) and beta(2) integrin-mediated adhesion in murine thymocytes. RhoA is also needed for integrin activation in vivo as loss of Rho function impaired the ability of thymocytes to adhere to the extracellular matrix protein VCAM-1 and prevented integrin activation induced by the GTPases Rac-1 and Rap1A in vivo. The regulated activity of integrins is needed for cell motility and in the present study it was seen that RhoA activity is critical for integrin-mediated thymocyte migration to chemokines in vitro. Thus, RhoA has a critical role in regulating cell adhesion and migration during T cell development.