Natural killer (NK) cells are a type of lymphocyte that spontaneously respond to stressed cells without any earlier exposure to an antigen by using their germline-encoded receptors.[1] NK cells are an important arm of the innate immune system and exert their effector functions as a standalone cell or in combination with other immune cells. They eliminate a range of cellular targets such as stressed, viral-infected, and cancer transformed cells.
NK cells are directly activated by different molecular signals generated by stimulatory and inhibitory receptors from macrophages, dendritic cells (DCs), eosinophils and T cells. This co-stimulation, or “crosstalk,” leads to NK cell activation and regulation of other innate and adaptive immune responses.
In this article, we will examine NK cell crosstalk with various immune cells and the associated signaling pathways.[2]
NK Cells Crosstalk with Dendritic Cells and T cells
The crosstalk between dendritic cells and NK cells plays a crucial role in triggering immune responses against several targets. This interaction works bi-directionally and greatly influences the subsequent adaptive immune responses.
Scientists from Gustave Roussy in France found that the pre-activation of NK cells by DCs is imperative for an effective immune response against tumors both in-vitro and in-vivo.[3] The same observation has been corroborated for viral infections.[4,5] Moreover, pattern recognition receptors (PRRs) of the innate immune system such as toll-like receptors (TLR) signaling participate in this DC-NK cross-talk by triggering the maturation of DCs and the secretion of various synergistic cytokines that subsequently activate NK cells.
Interaction of NK cells with immature dendritic cells (DCs) results in reciprocal activation as shown in the figure below. Mature DCs release IL-12 that efficiently promotes the secretion of IFN-γ by NK cells. The further secretion of IL-18 enhances the IL-12 effect by inducing IL-12 receptor on the surface of NK cells. Furthermore, IL-18 and IL-12 work synergistically to increase the cytolytic activity of NK cells and promote the polarization of Th1.[6,7] Upon activation, NK cells secrete more cytokines i.e., TNF and IFN-γ, that increase the maturation of DCs.
TNF consequently enhances the induction of co-stimulatory molecules on the surface of dendritic cells and synergizes with IFN-γ to trigger IL-12 production by DCs that works along with other cytokines to perform different functions as described earlier.[8,9] Further, IFN-γ induces the expression of IL-15 on the membrane of DCs that in turn helps in maintaining the survival and activation of both NK and T cells.[10] This loop continues and results in an improved innate immune response.
Figure 1. Crosstalk between NK Cells and Dendritic Cells
Crosstalk between Macrophages and NK Cells
Macrophages activate NK cells either by soluble mediators or cytokines i.e., IL-12 and IL-18, or by direct cell to cell connections.[11] Following a microbial infection, macrophages release several proinflammatory cytokines that activate NK cells including IL-18, IL-12, TNF-alpha, CCR7, and type I interferon.
Moreover, the polarization of naïve M0 and anti-inflammatory macrophages M2 to the proinflammatory macrophages M1 enhances the activation of NK cells resulting in an intense proinflammatory response.
As a result, stimulated NK cells eradicate other cells that express low MHC levels on their membrane such as virally infected cells and tumor cells. NK cells can also regulate the inflammatory response by inhibiting M1 in the presence of IL-10.[12,13]
Research Implications of NK Cell Crosstalk with Other Immune Cells
Co-culturing of Immune Cells
The crosstalk between NK cells with other immune cells can be effectively used in research to study the molecular signaling of the innate immune response and gain insight into cell-cell interactions using “cells co-culture.”
Research has shown that the co-culture of NK cells and monocytes or macrophages upregulated the expression of CD69 in NK cells that in turn activates them.[14-16] The activation occurs due to cell-cell contact and causes NK cells to release IFN-γ.[14,17] Thus, it can help mediate different cellular and therapeutic functions.
Cancer Immunotherapy
Research reported that co-culturing of NK cells and dendritic cells helps DCs to mature and release IL-12 and TNF as well as increases the levels of other costimulatory ligands i.e., CD86.[18] IL-12 mediate NK cells activation and these NK cells can serve as effective immunotherapy against cancer.[19]
Viral Infections
Recent research has provided evidence that NK and DCs crosstalk is compromised during HIV-1 infection. This defective cell communication involves abnormalities in the process of CD56neg NK cell activation through DCs and DCs maturation.[20] Other molecular mechanisms involved in this crosstalk can be targeted and studied using co-culture. The combination of NK-DC immunotherapy can be a promising cellular therapy in improving the immune functions in HIV-1 infection.
Conclusion
Studies performed on NK cells over the past decade have clearly shown that, during immune response, NK cells act by not only displaying their own protective functions, but also interacting with other immune cells to optimize the response against pathogens.
NK cells crosstalk with DCs and other immune cells through complex signaling pathways that fulfill complementary tasks. Ongoing research in this field is likely to yield greater understanding of NK activation and lead to advanced therapies for cancers and other diseases.
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References
[1] Ganesan, S., Regulation of Calcium Flux by Activating and Inhibitory Receptor Crosstalk in NK Cells. 2019, Karolinska Institutet (Sweden).[2] Malhotra, A. and A. Shanker, NK cells: immune cross-talk and therapeutic implications. Immunotherapy, 2011. 3(10): p. 1143-1166.
[3] Fernandez, N.C., et al., Dendritic cells (DC) promote natural killer (NK) cell functions: dynamics of the human DC/NK cell cross talk. European cytokine network, 2002. 13(1): p. 17-27.
[4] Lucas, M., et al., Natural killer cell-mediated control of infections requires production of interleukin 15 by type I IFN-triggered dendritic cells. Immunity, 2007. 26(4): p. 503.
[5] Kassim, S.H., et al., In vivo ablation of CD11c-positive dendritic cells increases susceptibility to herpes simplex virus type 1 infection and diminishes NK and T-cell responses. Journal of virology, 2006. 80(8): p. 3985-3993.
[6] Walzer, T., et al., Natural-killer cells and dendritic cells:“l’union fait la force”. Blood, 2005. 106(7): p. 2252-2258.
[7] Agaugué, S., et al., Human natural killer cells exposed to IL-2, IL-12, IL-18, or IL-4 differently modulate priming of naive T cells by monocyte-derived dendritic cells. Blood, The Journal of the American Society of Hematology, 2008. 112(5): p. 1776-1783.
[8] Gerosa, F., et al., Reciprocal activating interaction between natural killer cells and dendritic cells. The Journal of experimental medicine, 2002. 195(3): p. 327-333.
[9] Mailliard, R.B., et al., Dendritic cells mediate NK cell help for Th1 and CTL responses: two-signal requirement for the induction of NK cell helper function. The Journal of Immunology, 2003. 171(5): p. 2366-2373.
[10] Morandi, B., et al., NK cells provide helper signal for CD8+ T cells by inducing the expression of membrane-bound IL-15 on DCs. International immunology, 2009. 21(5): p. 599-606.
[11] Michel, T., F. Hentges, and J. Zimmer, Consequences of the crosstalk between monocytes/macrophages and natural killer cells. Frontiers in immunology, 2013. 3: p. 403.
[12] Bellora, F., et al., The interaction of human natural killer cells with either unpolarized or polarized macrophages results in different functional outcomes. Proceedings of the National Academy of Sciences, 2010. 107(50): p. 21659-21664.
[13] Eissmann, P., et al., Multiple mechanisms downstream of TLR-4 stimulation allow expression of NKG2D ligands to facilitate macrophage/NK cell crosstalk. The Journal of Immunology, 2010. 184(12): p. 6901-6909.
[14] Haller, D., et al., Activation of human NK cells by staphylococci and lactobacilli requires cell contact-dependent costimulation by autologous monocytes. Clinical and Vaccine Immunology, 2002. 9(3): p. 649-657.
[15] Dalbeth, N., et al., CD56bright NK cells are enriched at inflammatory sites and can engage with monocytes in a reciprocal program of activation. The Journal of Immunology, 2004. 173(10): p. 6418-6426.
[16] Scott, M., et al., CD40–CD154 interactions between macrophages and natural killer cells during sepsis are critical for macrophage activation and are not interferon gamma dependent. Clinical & Experimental Immunology, 2004. 137(3): p. 469-477.
[17] Atochina, O. and D. Harn, LNFPIII/LeX-stimulated macrophages activate natural killer cells via CD40-CD40L interaction. Clinical and Vaccine Immunology, 2005. 12(9): p. 1041-1049.
[18] Raulet, D.H., Interplay of natural killer cells and their receptors with the adaptive immune response. Nature immunology, 2004. 5(10): p. 996-1002.
[19] Amakata, Y., et al., Mechanism of NK cell activation induced by coculture with dendritic cells derived from peripheral blood monocytes. Clinical & Experimental Immunology, 2001. 124(2): p. 214-222.
[20] Mavilio, D., et al., Characterization of the defective interaction between a subset of natural killer cells and dendritic cells in HIV-1 infection. The Journal of experimental medicine, 2006. 203(10): p. 2339-2350.
