Review
NK cells and NKT cells in innate defense against viral infections

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Abstract

NK cells contribute to innate defense during certain viral infections, but the mechanisms for their regulation and delivery of antiviral effects are incompletely understood. A second NK cell population, from within T cell populations — NKT cells — has a unique potential to initiate cellular effector mechanisms, including those delivered by NK cells, provided that the antigen for their restricted TCR is induced during infection. If elicited, particular innate cytokine responses promote activation of NK cell cytotoxicity or IFN-γ production. These responses can contribute to defense by mediating antiviral and/or immunoregulatory effects. Roles of positive or negative receptors for target cells in protection against viruses are less clear. Exciting new data indicate that, in at least one system, NK cell receptors that positively signal for activation participate in the recruitment of these cells into antiviral defense mechanisms. Other recent evidence suggests that NKT cells may be important for protection during one viral infection and may be artificially activated by delivery of antigen to promote antiviral defense. Taken together, these recent advances in the characterization of the NK and NKT cell responses are filling in the details of the complex and critical events taking place, at the earliest times after challenge, to promote resistance to viruses.

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)

  • L Brossay et al.

    CD1d-mediated recognition of an α-galactosyl-ceramide by natural killer T-cells is highly conserved through mammalian evolution

    J Exp Med

    (1998)
  • G Eberl et al.

    Tissue-specific segregation of CD1d-dependent and CD1d-independent NK T-cells

    J Immunol

    (1999)
  • Biron CA, Dalod M, Salazar-Mather TP: Innate immunity and viral infections. In Immunity to Infections. Edited by...
  • D Rossi et al.

    The biology of chemokines and their receptors

    Annu Rev Immunol

    (2000)
  • E.M Bluman et al.

    Human natural killer cells produce abundant macrophage inflammatory protein-1 α in response to monocyte-derived cytokines

    J Clin Invest

    (1996)
  • A Oliva et al.

    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

    (1998)
  • T.A Fehniger et al.

    Natural killer cells from HIV-1+ patients produce C-C chemokines and inhibit HIV-1 infection

    J Immunol

    (1998)
  • L.P Cousens et al.

    Interferon-α/β inhibition of interleukin 12 and interferon-γ production in vitro and endogenously during viral infection

    Proc Natl Acad Sci USA

    (1997)
  • L.P Cousens et al.

    Two roads diverged: interferon α/β- and interleukin 12-mediated pathways in promoting T-cell interferon γ responses during viral infection

    J Exp Med

    (1999)
  • B.L McRae et al.

    Type I IFNs inhibit human dendritic cell IL-12 production and Th1 cell development

    J Immunol

    (1998)
  • J.S Orange et al.

    Characterization of early IL-12, IFN-αβ, and TNF effects on antiviral state and NK cell responses during murine cytomegalovirus infection

    J Immunol

    (1996)
  • K.B Nguyen et al.

    Interferon α/β-mediated inhibition and promotion of interferon γ: STAT1 resolves a paradox

    Nat Immunol

    (2000)
  • D.H Raulet et al.

    Regulation of the natural killer cell receptor repertoire

    Annu Rev Immunol

    (2001)
  • L.L Lanier

    On guard — activating NK cell receptors

    Nat Immunol

    (2001)
  • V.M Braud et al.

    HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C

    Nature

    (1998)
  • R.E Vance et al.

    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

    (1998)
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