Activation of natural killer cells during microbial infections

Abstract

Natural killer (NK) cells are large granular lymphocytes that express a diverse array of germline encoded inhibitory and activating receptors for MHC Class I and Class I-like molecules, classical co-stimulatory ligands, and cytokines. The ability of NK cells to be very rapidly activated by inflammatory cytokines, to secrete effector cytokines, and to kill infected or stressed host cells, suggests that they may be among the very early responders during infection. Recent studies have also identified a small number of pathogen-derived ligands that can bind to NK cell surface receptors and directly induce their activation. Here we review recent studies that have begun to elucidate the various pathways by which viral, bacterial, and parasite pathogens activate NK cells. We also consider two emerging themes of NK cell-pathogen interactions, namely their contribution to adaptive immune responses and their potential to take on regulatory and immunomodulatory functions.

Keywords: NK cells; activation; bacteria; infection; parasites; viruses.

Figure 1

Direct and indirect activation of NK cells. The “classical” pathway of NK cell activation (A,B) results from skewing of the balance between signals transmitted via inhibitory and activating receptors. Inhibitory receptors, such as the Ly49 lectin-like receptors in mice (A) and the killer cell immunoglobulin-like receptors (KIR) in humans (B) bind MHC class I molecules. These MHC class I molecules may contain either self or foreign (antigenic) peptides within the peptide binding groove and there is increasing evidence that the nature of the bound peptide may influence the affinity of receptor–MHC interactions. In the absence of appropriate inhibitory interactions (due to down regulation of MHC or expression of foreign MHC molecules which provide no ligands for polymorphic inhibitory receptors), activating signals may predominate, leading to production of effector molecules, and direct killing of target cells. Activating ligands include stress-induced ligands on infected or transformed cells and virus-encoded ligands. For example, during infection with murine cytomegalovirus (MCMV), the activating receptor Ly49H recognizes the MCMV-derived MHC class I-like molecule, m157, which leads to direct killing of MCMV-infected target cells [(A); lower panel]. The “indirect” pathway of NK cell activation results from contact-dependent and soluble signals derived from accessory cells and T cells transmitted to activating receptors on NK cells (C). Myeloid accessory cells recognize pathogens via PRRs, secrete cytokines, and upregulate co-stimulatory molecules. Accessory cells also present antigen to CD4+ T cells and provide T cell co-stimulation; activated T cells secrete IL-2 which synergizes with accessory cell signals to potentiate the activation of NK cells.

Figure 2

Nature killer cell activating signals from myeloid accessory cells and T cells. Following recognition of pathogen by PRRs, accessory cells (in blue, above) become activated and transmit signals (both contact-dependent and -independent) to activating receptors on NK cells (in purple, below). This figure summarizes those for which there is the strongest experimental evidence, but is not exhaustive.

Figure 3

Antigen-specific effector memory CD4⁺ T cells recruit NK cells as effector cells in adaptive immune responses. During primary infection, NK cells receive innate activation signals from myeloid accessory cells and make very limited responses (left). Upon re-exposure to a pathogen, antigen-specific CD4⁺ T cells are a potent and immediate source of IL-2. Accessory cell signals synergize with this IL-2, resulting in rapid and robust “adaptive” NK cell responses, including NK cell proliferation, secretion of effector molecules, and killing of affected target cells (right).

Figure 4

Environmental cues modulate pro-inflammatory and regulatory NK cell responses. Dendritic cells (DCs) infected with intracellular bacteria produce IL-12. (A) During localized infections, NK cells respond to IL-12 by producing IFN-γ, which amplifies the DC IL-12 response, creating an unregulated feedback loop. The pathogen is killed or contained but at the expense of significant tissue damage. (B) During systemic infection, as yet uncharacterized differences in the environmental cues provided by accessory cells (but possibly influenced by the concentration of IL-12) lead to NK cell production of IL-10. NK cell-derived IL-10 limits tissue damage but may also allow the infection to persist.