Natural killer cells in antiviral immunity

Abstract

Natural killer (NK) cells play an important role in innate immune responses to viral infections. Here, we review recent insights into the role of NK cells in viral infections, with particular emphasis on human studies. We first discuss NK cells in the context of acute viral infections, with flavivirus and influenza virus infections as examples. Questions related to activation of NK cells, homing to infected tissues and the role of tissue-resident NK cells in acute viral infections are also addressed. Next, we discuss NK cells in the context of chronic viral infections with hepatitis C virus and HIV-1. Also covered is the role of adaptive-like NK cell expansions as well as the appearance of CD56^- NK cells in the course of chronic infection. Specific emphasis is then placed in viral infections in patients with primary immunodeficiencies affecting NK cells. Not least, studies in this area have revealed an important role for NK cells in controlling several herpesvirus infections. Finally, we address new data with respect to the activation of NK cells and NK cell function in humans infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) giving rise to coronavirus disease 2019 (COVID-19).

Fig. 1. NK cell differentiation as a framework to understand NK cell antiviral immunity.

The differentiation status of human natural killer (NK) cells determines their functional response in viral infections. CD56^bright NK cells and less differentiated CD56^dim NK cells express high levels of NKG2A, natural cytotoxicity receptors (NCRs; NKp30, NKp44 and NKp46) and proinflammatory and antiviral cytokine receptors (IL-12 receptor (IL-12R), IL-18R and type I interferon receptor (IFNAR)). During acute viral infections, with ensuing production of IL-12, IL-18 and type I interferons by other immune cells, less differentiated NK cells are the main NK cell subset to respond. As indicated by black arrows, cytokine stimulation leads to signalling via signal transducer and activator of transcription 1 (STAT1) and STAT4 and PI3K–AKT–mTOR pathways to rapidly induce NK cell cytokine production and proliferation. With increased maturation, circulating CD56^bright NK cells undergo a phenotypic shift and their responsiveness during infection becomes altered. As a consequence, more differentiated NK cells are more prone to respond to cytomegalovirus, leading to the expansion of adaptive-like NK cells that express high levels of killer cell immunoglobulin-like receptors (KIRs) and NKG2C. Circulating CD56^bright NK cells might also home to tissues, giving rise to tissue-resident NK cells. Their role in the early response to infection remains elusive. However, liver-resident NK cells have been shown to mediate antigen-specific antiviral responses. Alterations in transcription factor expression during NK cell differentiation are indicated within the respective cell nuclei, and a summary of phenotypic changes during NK cell differentiation is depicted in the table. For some receptors, the expression depends on the tissue microenvironment and specific subsets studied and will deviate from what is indicated here (denoted by the asterisk). CLA, cutaneous lymphocyte-associated antigen; HAV, hepatitis A virus; HBV, hepatitis B virus; ISG, interferon-stimulated gene; NA, not available.

Fig. 2. NK cell deficiencies and viral infections.

Different genetic mutations have been linked to specific natural killer (NK) cell deficiencies. Affected genes encode either intranuclear proteins (GATA2, IRF8, RTEL1, GINS1, MCM4 and MCM10) or the surface-expressed Fc receptor for IgG CD16 (encoded by FCGR3A). Defects in the intranuclear proteins lead to disturbed NK cell development and/or differentiation. The mutation affecting CD16 causes altered NK cell functionality. A common denominator for NK cell deficiencies is an inappropriate response to viral infections, as evidenced by severe and/or recurrent herpesvirus infections (human cytomegalovirus (HCMV), Epstein–Barr virus (EBV), herpes simplex virus (HSV) and varicella zoster virus (VZV)), as well as human papillomavirus virus (HPV) infection and respiratory infections.

Fig. 3. NK cells in COVID-19.

In the circulation, natural killer (NK) cells respond strongly to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and display an altered phenotype, including elevated expression of activation markers (HLA-DR, CD69 and CD38), inhibitory molecules (TIM3, LAG3 and possibly PD1) and tissue-homing markers (CCR5, CXCR3 and CD62L). Furthermore, circulating NK cells are highly proliferative and upregulate perforin and granzyme B expression. This response is primarily confined to less differentiated NK cells, suggestive of a cytokine-driven response. NK cells likely home to the lungs, where they exhibit an inflamed transcriptional signature. In severe coronavirus disease 2019 (COVID-19), adaptive-like NK cells are found at higher frequencies in the circulation, but it remains unclear whether these cells home to the lungs and interact with infected epithelia that show increased expression of HLA-E, a ligand for the activating receptor NKG2C. Furthermore, the transcriptional profile of NK cells in the lung microenvironment of patients with severe COVID-19 is even further skewed towards inflammation. This lung microenvironment also contains high numbers of myeloid-derived suppressor cells (MDSCs) and immature neutrophils. However, details on how NK cells might interact with these cells remain elusive. Additional outstanding questions related to NK cells in COVID-19 are highlighted in the figure. CCL, CC-chemokine ligand; CCR, CC-chemokine receptor; CXCL, CXC-chemokine ligand; CXCR, CXC-chemokine receptor; KIR, killer cell immunoglobulin-like receptor; LAG3, lymphocyte activation gene 3; TIGIT, T cell immunoreceptor with immunoglobulin and ITIM domains; TIM3, T cell immunoglobulin mucin receptor 3.