Unraveling the dynamic mechanisms of natural killer cells in viral infections: insights and implications

Abstract

Viruses pose a constant threat to human well-being, necessitating the immune system to develop robust defenses. Natural killer (NK) cells, which play a crucial role in the immune system, have become recognized as vital participants in protecting the body against viral infections. These remarkable innate immune cells possess the unique ability to directly recognize and eliminate infected cells, thereby contributing to the early control and containment of viral pathogens. However, recent research has uncovered an intriguing phenomenon: the alteration of NK cells during viral infections. In addition to their well-established role in antiviral defense, NK cells undergo dynamic changes in their phenotype, function, and regulatory mechanisms upon encountering viral pathogens. These alterations can significantly impact the effectiveness of NK cell responses during viral infections. This review explores the multifaceted role of NK cells in antiviral immunity, highlighting their conventional effector functions as well as the emerging concept of NK cell alteration in the context of viral infections. Understanding the intricate interplay between NK cells and viral infections is crucial for advancing our knowledge of antiviral immune responses and could offer valuable information for the creation of innovative therapeutic approaches to combat viral diseases.

Keywords: Antiviral immunity; Chronic infection; Innate immune response; NK cell alteration; Natural killer cells; Viral infections.

Fig. 1

A Developmental pathway of NK cells. The developmental pathway of NK cells from the bone marrow involves an ongoing process of differentiation and maturation. It begins with hematopoietic stem cells (HSCs) residing in the bone marrow, which serve as the origin for NK cell development. Firstly, HSCs differentiate into Lymphoid-primed Multipotent Progenitors (LMPPs). Subsequently, LMPPs give rise to Common Lymphoid Progenitors (CLPs), which possess the ability to develop into various lymphoid lineages, including NK cells. Following the emergence of NK cell progenitors from CLPs, the developmental process continues onward. Subsequently, these NK cell progenitors undergo further differentiation, resulting in the formation of mature NK cells. These mature NK cells are identifiable by their expression of CD56 and CD16. B In vitro, human NK cells can differentiate into two distinct functional subsets known as NK1 and NK2. When cultured with IL-12 and IL-18, NK cells (NK1) primarily generate IFN-γ, while those cultured with IL-4 (NK2) predominantly produce IL-5 and IL-13. C Human NK cells can be categorized into three distinct functional subsets based on their roles, specifically referred to as NK tolerant, NK cytotoxic, and NK regulatory. Figure created using BioRender (Created with biorender.com)

Fig. 2

Mechanisms of target recognition by NK cells and subsequent activation. Their activation is tightly regulated and involves a complex interplay of activating and inhibitory signals. “Normal circumstance”: NK cells recognize autologous MHC class I molecules through inhibitory receptors like killer cell immunoglobulin-like receptor (KIR), indicating the interaction with normal cells and suppressing their activation. “Missing-self”: NK cells recognize target cells that either lack expression or have reduced levels of MHC class I molecules, such as infected or transformed cells. This recognition leads to the activation of NK cells. “Stress-induced”: NK cells recognize activating ligands expressed on target cells through NK receptors like NKG2D. This recognition can override MHC class I-mediated inhibitory signaling, resulting in the activation of NK cells. “Non-self”: NK cells recognize transplanted tissue when the donor tissue expresses either allogeneic or haploidentical MHC class I molecules. Figure created using BioRender (Created with biorender.com/)

Fig. 3

A, B NK cells mechanism of actions for cytolytic purpose. NK cells employ multiple mechanisms of action to exert their cytolytic function against target cells. These mechanisms involve a coordinated interplay of activating and inhibitory signals, leading to target cell recognition, activation, and destruction. The primary mechanisms of NK cell-mediated cytotoxicity include: (1) Release of Cytotoxic Granules, (2) Death Receptor Pathway, and (3) ADCC. C Viral mechanisms for evading NK cell: (1) Elevating the levels of inhibitory ligands (including HLA-E and HLA-C) and decreasing the presence of activating ligands (including ULBP1, ULBP2, MIC-A MIC-B) on the infected cell. (2) Viral products or cytokines released from infected cells have the ability to alter the quantity of receptors on NK cells. This alteration involves an increase in the expression of inhibitory receptors such as NKG2A and a decrease in the expression of activating receptors such as NKG2D on the infected cell. (3) Several viruses have the ability to directly disrupt the functioning of NK cells by infecting them. Viral infection can induce immune suppression, either by suppressing the cytotoxic function of NK cells or by initiating apoptosis, resulting in the depletion of NK cells