Trends in Immunology
Volume 29, Issue 8, August 2008, Pages 397-403
Journal home page for Trends in Immunology

Review
NKG2D ligands: key targets of the immune response

https://doi.org/10.1016/j.it.2008.04.007Get rights and content

NKG2D is an activating receptor expressed by NK and T cells. NKG2D ligands show a restricted expression in normal tissues, but they are frequently overexpressed in cancer and infected cells. The binding of NKG2D to its ligands activates NK and T cells and promotes cytotoxic lysis of the cells expressing these molecules. The mechanisms involved in the expression of the ligands of NKG2D play a key role in the recognition of stressed cells by the immune system and represent a promising therapeutic target for improving the immune response against cancer or autoimmune disease. In this review, we analyse the recent advances in understanding the regulation of NKG2D ligand expression and their therapeutic implications.

Section snippets

Structure and function of NKG2D ligands

Natural killer (NK) cell function is regulated by a delicate balance of signals initiated from a variety of activating and inhibitory receptors. NKG2D is an activating receptor expressed by NK cells, CD8+ TCR (T cell receptor) αβ and γδT cells 1, 2, 3, 4. In NK cells, NKG2D serves as a primary activation receptor, which is by itself able to trigger cytotoxicity. In CD8 T cells, NKG2D acts as a co-stimulatory receptor of TCR-activated cells. However, it has been also reported that, depending on

Transcriptional regulation of NKG2DL expression

The ligands of NKG2D are frequently overexpressed in tumors from multiple origins 6, 12, 13, 18, 21, 22, 23, 24, 25, 26, 27. The central role of tumor suppressor and oncogenes in the pathogenesis of cancer suggests that these might be the main candidates for the induction of NKG2DL expression in transformed cells. In chronic myeloid leukemia, the BCR/ABL (breakpoint cluster region/abelson) fusion oncoprotein induces the expression of MICA on the surface of leukemic cells, but it is absent on

Stimuli involved in the upregulation of NKG2D ligands

The first insight into the regulation of NKG2DL was the finding that MICA/B promoters resembled those of heat shock protein 70 (HSP70) and that heat shock induces MICA expression [18] (Table 1). This finding provides the first evidence that NKG2D is able to detect cellular stress, which is a status frequently associated with cancer and infection. Similarly, NKG2DL expression is upregulated in response to oxidative stress 42, 43 and is also induced in nontumor cell lines by genotoxic stress and

Diversity of NKG2D ligands

A characteristic of the NKG2D system is that there are multiple ligands for this receptor [56]. A key question regarding NKG2D is why such a diversity of ligands exists. Common sense suggests that the redundancy of NKG2DLs may reflect a mechanism to counter immune evasion by pathogens. In this regard, human cytomegalovirus (HCMV) has evolved proteins such as UL16 that cause the intracellular retention of MICB, ULBP1 and ULBP2, but not MICA and ULBP3 57, 58, 59 and UL142, which is able to retain

Impairment of NKG2DL function in cancer

The immune system is able to kill cancer cells. However, if the tumor is not completely eliminated, the immune system ends up ‘sculpting’ or ‘editing’ the phenotype of the tumor, resulting in elimination of the most immunogenic cancer cells and favoring the development of nonimmunogenic tumors [39]. Therefore, the first observation that MICA is broadly expressed on multiple primary tumors was paradoxical [12]. Nevertheless, a systemically diminished NKG2D expression on T and NK cells was

Concluding remarks

Although MHC molecules present peptides to T cells, NKG2DLs are upregulated in response to cellular stress, which is usually caused by infection or cellular transformation. To analyse the mechanisms and pathways involved in the regulation of these genes, the promoter architecture and transcriptional regulation of several ligands of NKG2D have been recently analysed. Unexpectedly, these genes are essentially regulated by ubiquitous transcription factors. However, the current information suggests

Acknowledgements

This work was supported by the Spanish grants of Fondo de Investigaciones Sanitarias PI-06/0841, FICYT PC-06/010 and “Fundación Mútua Madrileña 2007-2009” and Red de Investigación Renal REDinREN (RD06/0016). A.L.S. holds a predoctoral fellowship from FICYT of Asturias (ref. BP06-99).

References (72)

  • C. Cerboni

    Antigen-activated human T lymphocytes express cell-surface NKG2D ligands via an ATM/ATR-dependent mechanism and become susceptible to autologous NK- cell lysis

    Blood

    (2007)
  • C.L. Sutherland

    ULBPs, human ligands of the NKG2D receptor, stimulate tumor immunity with enhancement by IL-15

    Blood

    (2006)
  • E.P. Von Strandmann

    A novel bispecific protein (ULBP2-BB4) targeting the NKG2D receptor on natural killer (NK) cells and CD138 activates NK cells and has potent antitumor activity against human multiple myeloma in vitro and in vivo

    Blood

    (2006)
  • N.J. Chalupny

    Down-regulation of the NKG2D ligand MICA by the human cytomegalovirus glycoprotein UL142

    Biochem. Biophys. Res. Commun.

    (2006)
  • M. Radosavljevic

    A cluster of ten novel MHC class I related genes on human chromosome 6q24

    2-q25. 3. Genomics

    (2002)
  • A. Cerwenka et al.

    Ligands for natural killer cell receptors: redundancy or specificity

    Immunol. Rev.

    (2001)
  • A. Diefenbach et al.

    H. Strategies for target cell recognition by natural killer cells

    Immunol. Rev.

    (2001)
  • D.H. Raulet

    Roles of the NKG2D immunoreceptor and its ligands

    Nat. Rev. Immunol.

    (2003)
  • S. Gonzalez

    Immunobiology of human NKG2D and its ligands

    Curr. Top. Microbiol. Immunol.

    (2006)
  • S. Bahram

    A second lineage of mammalian major histocompatibility complex class I genes

    Proc. Natl. Acad. Sci. U. S. A.

    (1994)
  • V. Groh

    Recognition of stress-induced MHC molecules by intestinal epithelial gammadelta T cells

    Science

    (1998)
  • S. Bauer

    Expression, purification, crystallization and crystallographic characterization of the human MHC class I related protein MICA

    Acta Crystallogr. D Biol. Crystallogr.

    (1998)
  • N.J. Chalupny

    ULBP4 is a novel ligand for human NKG2D

    Biochem. Biophys. Res. Commun.

    (2003)
  • L. Bacon

    Two human ULBP/RAET1 molecules with transmembrane regions are ligands for NKG2D

    J. Immunol.

    (2004)
  • Z. Li

    A single amino acid substitution causes loss of expression of a MICA allele

    Immunogenetics

    (2000)
  • V. Groh

    Broad tumor-associated expression and recognition by tumor-derived gamma delta T cells of MICA and MICB

    Proc. Natl. Acad. Sci. U. S. A.

    (1999)
  • S. Bauer

    Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA

    Science

    (1999)
  • M.J. Smyth

    NKG2D function protects the host from tumor initiation

    J. Exp. Med.

    (2005)
  • D.E. Oppenheim

    Sustained localized expression of ligand for the activating NKG2D receptor impairs natural cytotoxicity in vivo and reduces tumor immunosurveillance

    Nat. Immunol.

    (2005)
  • A. Diefenbach

    Rae1 and H60 ligands of the NKG2D receptor stimulate tumour immunity

    Nature

    (2001)
  • A. Cerwenka

    Ectopic expression of retinoic acid early inducible-1 gene (RAE-1) permits natural killer cell-mediated rejection of a MHC class I-bearing tumor in vivo

    Proc. Natl. Acad. Sci. U. S. A.

    (2001)
  • V. Groh

    Cell stress-regulated human major histocompatibility complex class I gene expressed in gastrointestinal epithelium

    Proc. Natl. Acad. Sci. U. S. A.

    (1996)
  • S. Gasser

    The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor

    Nature

    (2005)
  • V. Groh

    Costimulation of CD8alphabeta T cells by NKG2D via engagement by MIC induced on virus-infected cells

    Nat. Immunol.

    (2001)
  • A. Busche

    Natural killer cell-mediated rejection of experimental human lung cancer by genetic overexpression of major histocompatibility complex class I chain-related gene A

    Hum. Gene Ther.

    (2006)
  • D. Pende

    Major histocompatibility complex class I-related chain A and UL16-binding protein expression on tumor cell lines of different histotypes: analysis of tumor susceptibility to NKG2D-dependent natural killer cell cytotoxicity

    Cancer Res.

    (2002)
  • Cited by (0)

    View full text