Cytokine and contact-dependent activation of natural killer cells by influenza A or Sendai virus-infected macrophages

Abstract

NK cells participate in innate immune responses by secreting gamma interferon (IFN-c) and by destroying virus-infected cells. Here the interaction between influenza A or Sendai virus-infected macrophages and NK cells has been studied. A rapid, cell-cell contact-dependent production of IFN-c from NK cells cultured with virus-infected macrophages was observed. Expression of the MHC class I-related chain B (MICB) gene, a ligand for NK cell-activating receptor NKG2D, was upregulated in virus-infected macrophages suggesting a role for MICB in the activation of the IFN-c gene in NK cells. IL12Rb2, IL18R and T-bet mRNA synthesis was enhanced in NK cells cultured with virus-infected macrophages. Upregulation of these genes was dependent on macrophage-derived IFN-a. In contrast to IL12Rb2, expression of WSX-1/TCCR, a receptor for IL27, was reduced in NK cells in response to virus-induced IFN-a. In conclusion, these results show that virus-infected macrophages activate NK cells via cytokines and direct cellular interactions and further emphasize the role of IFN-a in the activation of innate immunity. INTRODUCTIONNK cells function as a key factor in immediate immune responses to intracellular pathogens, such as viruses (Trinchieri, 1989). The vital role of NK cells in controlling virus infections was demonstrated in a patient completely lacking NK cells and sustaining severe herpesvirus infections (Biron et al., 1989). Besides their lytic potential, activated NK cells secrete cytokines and chemokines (Cooper et al., 2001). NK cell-derived gamma interferon (IFN-c) drives Th1-type immunity and activates macrophages. Activated macrophages in turn produce IFN-a, interleukin (IL)12 and IL18 (Biron, 1999; Pirhonen et al., 1999;Sareneva et al., 1998;Trinchieri, 1997). These cytokines regulate NK cell activation and IFN-c production (Biron, 1998;Biron et al., 1999;Matikainen et al., 2001;Nguyen et al., 2002;Orange & Biron, 1996) Besides cytokines, cellular interactions regulate NK cell effector functions. NK cells express several inhibitory receptors specific for MHC class I molecules (Colonna, 1996;Long, 1999;Moretta et al., 1996;Moretta & Moretta, 1997;Ravetch & Lanier, 2000), which are frequently downregulated in virus-infected cells (Tortorella et al., 2000). In addition, activating receptors have been identified in NK cells. In humans these include the natural cytotoxicity receptors (NCRs) Nkp30, Nkp44 and Nkp46 and NKG2D . Cellular ligands for NCRs are not known, whereas NKG2D recognizes the stress-inducible MHC class I-related chain A and B (MICA/B) (Bauer et al., 1999;Wu et al., 1999) and UL-16 binding proteins (ULBPs) (Cosman et al., 2001;Sutherland et al., 2002). The balance between activating and inhibiting signals from cellular interactions and soluble mediators determines NK cell responses.Here we have investigated the interaction between virusinfected macrophages and NK cells. We demonstrate that both cell-cell contact and macrophage-derived IFN-a regulates NK cell responses during early stages of infection. METHODS...

Positive and Negative Regulation of the IL-27 Receptor during Lymphoid Cell Activation

“…Thus, to explore a role for IL-27 in this parasite-induced inflammation, surface levels of WSX-1 were monitored on NK cells before and after challenge with T. gondii (day 5 , it is apparent that expression of the IL-27R is suppressed only after these cells become activated. Consistent with these findings, expression of WSX-1 mRNA is reduced after NK cells are stimulated by virally challenged macrophages (25).…”

Inhibition of Human Natural Killer Cell Activity by Influenza Virions and Hemagglutinin

“…However, the activation of NK cells is dependent on the cytokines released from infected cells as well as the interaction between NK cell receptors (NKG2D and NKp46) and the corresponding ligands expressed on the surface of infected accessory cells. Among the cytokines, alpha interferon is responsible for enhanced NK cytotoxicity (27,39,69). To dissect the direct effects of influenza virus on NK cells, purified primary human NK cells were used in this study to exclude the effects of accessory cells.…”

The type I interferon system in systemic lupus erythematosus

“…This facilitates antigen presentation, homing to lymphoid organs, and activation of immune cells. Helper T cells are in this way stimulated and develop along the Th1 pathway, at least in part because type I IFN stimulates expression of the IL-12 receptor and transcription factor T-bet, which counteract the GATAdependent Th2 default pathway (28,29). Type I IFNs also markedly stimulate development of cytotoxic T cells, in part because of an increased cross-presenting function of dendritic cells (30) and prevention of apoptosis of activated T cells (31,32).…”