ReviewNK cells and NKT cells in innate defense against viral infections
Introduction
NK cells can contribute to innate defense against viral infections because they are poised to rapidly respond as populations to early events following challenge. The first class of NK cells that were identified—classical NK cells —are non-T-cell lymphocytes, lacking expression of TCRs [1]. These cells can develop under conditions that limit T cell development. They express a variety of cell surface markers, including CD56 in the human and NK1.1 or DX5 in the mouse, and a complex family of polymorphic, nonvariant receptors first identified based on their recognition of classical MHC molecules [2]. NK cells are dependent upon the bone marrow for development and are present as mature populations in blood and spleen. They are generally found at low frequencies in lymph nodes but can be induced to accumulate at these sites following local stimulation.
A second set of NK cells — NKT cells — has been more recently identified; these cells are found within T cell populations and identification is based on expression of TCR molecules and certain NK cell markers, particularly NK1.1 in the mouse [3]. In addition to NK1.1, they express a variety of markers overlapping with classical NK cells, including DX5 in the mouse and the nonvariant receptors recognizing MHC molecules. In contrast to NK cells, NKT cells are dependent on the machinery and environment needed to support T cell maturation. They are also dependent on the nonclassical-MHC-class-I-like molecule, CD1d, for development 3., 4.. NKT cells have a restricted TCR repertoire. They have the unusual property of being readily stimulated through their TCR as a result of presentation of the nonpeptide antigen, α-galactosylceramide (α-GalCer), by CD1d molecules 5., 6., 7.. NKT cells constitute small percentages of the T cells found in thymus and spleen but a significant proportion of those in the liver [8].
Extensive work has been done to define the responses and functions of classical NK cells during a variety of viral infections 1., 9.. Although much remains to be learned, the mechanisms contributing to their activation and functions under these conditions are being elucidated at the molecular level. Much less is known about the responses and functions of NKT cells during viral infections, but these are beginning to be characterized. The recent advances in understanding the importance of NK and NKT cell in defense against viral infections are reviewed here. Because reports during the past year have made particularly significant advances in characterizing, firstly, the functions of the nonvariant receptors, secondly, the pathways used by NK cells to mediate antiviral defense and, thirdly, the activation and functions of NKT cells, the focus is on these topics.
Section snippets
Innate cytokines and the control of NK cell antiviral defense
Classical NK cells clearly play a role in the control of some, but not all, mouse and human viruses. The best evidence for their function is in defense against the herpes-group viruses [1]. Type I interferons (IFN-α/β)—innate cytokines elicited in response to certain viral infections and important for inhibition of viral replication—also enhance NK cell mediated cytotoxicity such that a broader range of target cells, including virus-infected cells, are lysed. Interestingly, however, a clear
An overview of antiviral responses and functions of NKT cells
NKT cells are a T cell subset that express markers associated with NK cells (NK1.1 and Ly-49), exhibit an activated phenotype (CD44highLy6ChighIL-2Rβ high) and display a restricted TCR repertoire. NKT cells are selected by the nonclassical-MHC-class-I-like molecule, CD1d, which in mice is expressed on dendritic cells, B cells, T cells, macrophages and hepatocytes 3., 4.. The majority of murine NKT cells express a so-called ‘invariant’ Vα chain in their TCR, which in mice is formed as a result
Conclusions
Significant advances have been recently made in understanding the functions of NK and NKT cells for innate defense against viral infections (Fig. 1). NK cells are activated in response to innate cytokines. Their responses have the potential to mediate defense through both direct antiviral and immunoregulatory pathways. It is becoming clear that members of the NK cell receptor family can contribute to promoting NK-cell-mediated antiviral defense mechanisms, but much remains to be learned about
Acknowledgements
Work from Christine Biron's laboratory is supported in part by US Public Health Service Grants CA41268, MH47674 and AI44644. Work from Laurent Brossay's laboratory is supported in part by US Public Health Service Grant AI46709 and RR15578.
References and recommended reading
Papers of particular interest, published within the annual period of review,have been highlighted as:
•of special interest
••of outstanding interest
References (53)
- et al.
Murine CD1d-restricted T-cell recognition of cellular lipids
Immunity
(2000) - et al.
Interferon β in multiple sclerosis: is IL-12 suppression the key?
Immunol Today
(2000) - et al.
Genetic mapping of Cmv1 in the region of mouse chromosome 6 encoding the NK gene complex-associated loci Ly49 and musNKR-P1
Genomics
(1995) - et al.
ULBPs, novel MHC class I-related molecules, bind to CMV glycoprotein UL16 and stimulate NK cytotoxicity through the NKG2D receptor
Immunity
(2001) - et al.
Rapid death and regeneration of NKT-cells in anti-CD3- or IL-12-treated mice: a major role for bone marrow in NK T-cell homeostasis
Immunity
(1998) - et al.
Natural killer cells in antiviral defense: function and regulation by innate cytokines
Annu Rev Immunol
(1999) NK cell receptors
Annu Rev Immunol
(1998)- et al.
Mouse CD1-specific NK1 T-cells: development, specificity, and function
Annu Rev Immunol
(1997) - et al.
The CD1 system: antigen-presenting molecules for T-cell recognition of lipids and glycolipids
Annu Rev Immunol
(1999) - et al.
CD1d-restricted and TCR-mediated activation of Vα14 NKT-cells by glycosylceramides
Science
(1997)
CD1d-mediated recognition of an α-galactosyl-ceramide by natural killer T-cells is highly conserved through mammalian evolution
J Exp Med
Tissue-specific segregation of CD1d-dependent and CD1d-independent NK T-cells
J Immunol
The biology of chemokines and their receptors
Annu Rev Immunol
Human natural killer cells produce abundant macrophage inflammatory protein-1 α in response to monocyte-derived cytokines
J Clin Invest
Natural killer cells from human immunodeficiency virus (HIV)-infected individuals are an important source of CC-chemokines and suppress HIV-1 entry and replication in vitro
J Clin Invest
Natural killer cells from HIV-1+ patients produce C-C chemokines and inhibit HIV-1 infection
J Immunol
Interferon-α/β inhibition of interleukin 12 and interferon-γ production in vitro and endogenously during viral infection
Proc Natl Acad Sci USA
Two roads diverged: interferon α/β- and interleukin 12-mediated pathways in promoting T-cell interferon γ responses during viral infection
J Exp Med
Type I IFNs inhibit human dendritic cell IL-12 production and Th1 cell development
J Immunol
Characterization of early IL-12, IFN-αβ, and TNF effects on antiviral state and NK cell responses during murine cytomegalovirus infection
J Immunol
Interferon α/β-mediated inhibition and promotion of interferon γ: STAT1 resolves a paradox
Nat Immunol
Regulation of the natural killer cell receptor repertoire
Annu Rev Immunol
On guard — activating NK cell receptors
Nat Immunol
HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C
Nature
Mouse CD94/NKG2A is a natural killer cell receptor for the nonclassical major histocompatibility complex (MHC) class I molecule Qa-1(b)
J Exp Med
Cited by (380)
Cellular infiltration, cytokines, and histopathology of skin lesions associated with different clinical forms and stages of naturally occurring lumpy skin disease in cattle
2022, Comparative Immunology, Microbiology and Infectious DiseasesA semen-based stimulation method to analyze cytokine production by uterine CD56<sup>bright</sup> natural killer cells in women with recurrent pregnancy loss
2020, Journal of Reproductive ImmunologyCitation Excerpt :Reproductive performance might be negatively influenced by immunologically dysfunctional NK cells, including impaired structure and dysregulated cytokine production (Fukui et al., 2008; Raghupathy et al., 2000; Seshadri and Sunkara, 2014). The NK cells are classified as CD56dim and CD56bright cells according to the surface density of the CD56 antigen (Biron and Brossay, 2001; Lodoen and Lanier, 2006). CD56dim cells are predominant in peripheral blood and are associated with cytotoxicity, whereas CD56bright cells that are mainly located in the uterine endometrium and decidua, are associated with cytokine production (Caligiuri, 2008; Cooper et al., 2001; Fukui et al., 2017).