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Review
. 2023 Sep 25;21(1):261.
doi: 10.1186/s12964-023-01266-2.

Natural killer cells and their exosomes in viral infections and related therapeutic approaches: where are we?

Mohammad Hossein Razizadeh #  1   2 , Alireza Zafarani #  3 , Mahsa Taghavi-Farahabadi  4 , Hossein Khorramdelazad  5   6 , Sara Minaeian  7 , Mohammad Mahmoudi  8   9
Affiliations
Review

Natural killer cells and their exosomes in viral infections and related therapeutic approaches: where are we?

Mohammad Hossein Razizadeh et al. Cell Commun Signal. .

Abstract

Innate immunity is the first line of the host immune system to fight against infections. Natural killer cells are the innate immunity lymphocytes responsible for fighting against virus-infected and cancerous cells. They have various mechanisms to suppress viral infections. On the other hand, viruses have evolved to utilize different ways to evade NK cell-mediated responses. Viruses can balance the response by regulating the cytokine release pattern and changing the proportion of activating and inhibitory receptors on the surface of NK cells. Exosomes are a subtype of extracellular vesicles that are involved in intercellular communication. Most cell populations can release these nano-sized vesicles, and it was shown that these vesicles produce identical outcomes to the originating cell from which they are released. In recent years, the role of NK cell-derived exosomes in various diseases including viral infections has been highlighted, drawing attention to utilizing the therapeutic potential of these nanoparticles. In this article, the role of NK cells in various viral infections and the mechanisms used by viruses to evade these important immune system cells are initially examined. Subsequently, the role of NK cell exosomes in controlling various viral infections is discussed. Finally, the current position of these cells in the treatment of viral infections and the therapeutic potential of their exosomes are reviewed. Video Abstract.

Keywords: Exosome; Extracellular vesicles; Immune evasion; Innate immunity; NK cells; Virus.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Viral infections have different ways of evading the immune response by the NK cells. A They can alter the proportion of ligands on the cell surface of infected cells to change the NK cell response after interacting with the infected cells from activation to inhibition. B Also, they can use cytokines and viral proteins to send inhibitory signals to the NK cells. C Some viruses can also directly infect the NK cells and induce apoptosis
Fig. 2
Fig. 2
NK cells can secrete exosomes with various cargo. These exosomes contain TSG101, Alix, CD9, CD63, CD81, and CD82. In addition to typical exosome markers, NK cell-derived exosomes exhibit specific biomarkers such as CD56, DNAM-1, NKp30, NKp44, NKp46, and NKG2D. NK cell-derived exosomes contain perforin and express FasL, which contribute to the cytotoxicity effects of these vesicles. Cytotoxic proteins such as perforin, granzyme A, granzyme B, and granulysin can induce apoptosis in target cells. Since the mechanism of action of NK cells and their exosomes against tumor and virus-infected cells is relatively similar, it seems that NK cell exosomes use the following mechanisms to fight against virus-infected cells. NK cell derived-exosomes can overexpress the NK activating receptors NKp30, NKp44, NKp46, and NKG2D and be able to educate naïve NK cells, which evolve into a memory-like state, with increased cytotoxicity and enhanced tumor-killing capacity. NK cell-derived exosomes were rich in miR-10b-5p, miR-155-5p, or miR-92a-3p. T cell response can be the putative target of these small RNAs. So, NK cell-derived exosomes promote Th1 differentiation and increase IL-2 and IFN-γ production. On the other hand, the polarization of monocyte to monocyte-derived dendritic cells can be affected by NK cell-derived exosomes, and these vesicles increased the expression of MHC-II and CD86 on these cells. NK cell-derived exosomes can shift macrophage polarization to M1. As mentioned, the existence of FasL and TRAIL on the surface of NK cell-derived exosomes and cargo of perforin, granzyme A, granzyme B, and granulysin were confirmed by multiple studies supporting direct cytotoxic effects of NK cell exosomes in the face of target cells. miRNAs are another tools that these valuable exosomes use to inhibit target cells
Fig. 3
Fig. 3
Strengthening the host immune system by therapeutic approaches that augment NK cells’ cytotoxicity and longevity or transferring of the functional NK cells
See this image and copyright information in PMC

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