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Tumour-derived soluble MIC ligands impair expression of NKG2D and T-cell activation


Engagement of the NKG2D receptor by tumour-associated ligands may promote tumour rejection by stimulating innate and adaptive lymphocyte responses1,2,3,4,5. In humans, NKG2D is expressed on most natural killer cells, γδ T cells and CD8αβ T cells1. Ligands of NKG2D include the major histocompatibility complex class I homologues MICA and MICB, which function as signals of cellular stress6,7. These molecules are absent from most cells and tissues but can be induced by viral and bacterial infections and are frequently expressed in epithelial tumours8,9,10,11. MIC engagement of NKG2D triggers natural killer cells and costimulates antigen-specific effector T cells1,10. Here we show that binding of MIC induces endocytosis and degradation of NKG2D. Expression of NKG2D is reduced markedly on large numbers of tumour-infiltrating and matched peripheral blood T cells from individuals with cancer. This systemic deficiency is associated with circulating tumour-derived soluble MICA, causing the downregulation of NKG2D and in turn severe impairment of the responsiveness of tumour-antigen-specific effector T cells. This mode of T-cell silencing may promote tumour immune evasion and, by inference, compromise host resistance to infections.

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Figure 1: Reduced expression of NKG2D on CD8+ αβ T cells among TILs and PBMCs from individuals with MIC-positive tumours.
Figure 2: MIC-induced downregulation and degradation of NKG2D.
Figure 3: Detection of sMICA by ELISA in serum samples from individuals with MIC-positive tumours and reduced expression of NKG2D.
Figure 4: Downregulation of NKG2D by rsMICA.
Figure 5: Downregulation of NKG2D by sera from individuals with MIC-positive tumours.
Figure 6: Functional impairment of NKG2Dlow T cells.


  1. Bauer, S. et al. Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science 285, 727–729 (1999)

    Article  CAS  Google Scholar 

  2. Cerwenka, A., Baron, J. L. & Lanier, L. L. Ectopic expression of retinoic acid early inducible-1 gene (RAE-1) permits natural killer cell-mediated rejection of a MHC class I-bearing tumour in vivo. Proc. Natl Acad. Sci. USA 98, 11521–11526 (2001)

    Article  ADS  CAS  Google Scholar 

  3. Diefenbach, A., Jensen, E. R., Jamieson, A. M. & Raulet, D. H. Rae1 and H60 ligands of the NKG2D receptor stimulate tumour immunity. Nature 413, 165–171 (2001)

    Article  ADS  CAS  Google Scholar 

  4. Long, E. O. Tumor cell recognition by natural killer cells. Sem. Cancer Biol. 12, 57–61 (2002)

    Article  CAS  Google Scholar 

  5. Pardoll, D. M. Stress, NK receptors, and immune surveillance. Science 294, 534–536 (2002)

    Article  Google Scholar 

  6. Groh, V. et al. Cell stress-regulated human major histocompatibility complex class I gene expressed in gastrointestinal epithelium. Proc. Natl Acad. Sci. USA 93, 12445–12450 (1996)

    Article  ADS  CAS  Google Scholar 

  7. Groh, V., Steinle, A., Bauer, S. & Spies, T. Recognition of stress-induced MHC molecules by intestinal epithelial γδ T cells. Science 279, 1737–1740 (1998)

    Article  ADS  CAS  Google Scholar 

  8. Groh, V. et al. Broad tumour-associated expression and recognition by tumour-derived γδ T cells of MICA and MICB. Proc. Natl Acad. Sci. USA 96, 6879–6884 (1999)

    Article  ADS  CAS  Google Scholar 

  9. Das, H. et al. MICA engagement by human Vγ2Vδ2 T cells enhances their antigen-dependent effector function. Immunity 15, 83–93 (2001)

    Article  CAS  Google Scholar 

  10. Groh, V. et al. Costimulation of CD8 αβ T cells by NKG2D via engagement by MIC induced on virus-infected cells. Nature Immunol. 2, 255–260 (2001)

    Article  ADS  CAS  Google Scholar 

  11. Tieng, V. et al. Binding of Escherichia coli adhesin AfaE to CD55 triggers cell-surface expression of the MHC class I-related molecule MICA. Proc. Natl Acad. Sci. USA 99, 2977–2982 (2002)

    Article  ADS  CAS  Google Scholar 

  12. Linsley, P. S., Bradshaw, J., Urnes, M., Grosmaire, L. & Ledbetter, J. A. CD28 engagement by B7/BB-1 induces transient down-modulation of CD28 synthesis and prolonged unresponsiveness to CD28 signaling. J. Immunol. 150, 3161–3169 (1993)

    CAS  PubMed  Google Scholar 

  13. Valitutti, S., Muller, S., Salio, M. & Lanzavecchia, A. Degradation of T cell receptor (TCR)–CD3-ζ complexes after antigenic stimulation. J. Exp. Med. 185, 1859–1864 (1997)

    Article  CAS  Google Scholar 

  14. Huard, B. & Karlsson, L. KIR expression on self-reactive CD8+ T cells is controlled by T-cell receptor engagement. Nature 403, 325–328 (2000)

    Article  ADS  CAS  Google Scholar 

  15. Li, P. et al. Complex structure of the actiavting immunoreceptor NKG2D and its MHC class I–like ligand MICA. Nature Immunol. 2, 443–451 (2001)

    Article  CAS  Google Scholar 

  16. Steinle, A. et al. Interactions of human NKG2D with its ligands MICA and MICB and homologs of the mouse RAE-1 protein family. Immunogenetics 53, 279–287 (2001)

    Article  CAS  Google Scholar 

  17. Wu, J. et al. An activating immmunoreceptor complex formed by NKG2D and DAP10. Science 285, 730–732 (1999)

    Article  CAS  Google Scholar 

  18. Yee, C., Savage, P. A., Lee, P. P., Davis, M. M. & Greenberg, P. D. Isolation of high avidity melanoma-reactive CTL from heterogeneous populations using peptide-MHC tetramers. J. Immunol. 162, 2227–2234 (1999)

    CAS  PubMed  Google Scholar 

  19. Schatz, P. J. Use of peptide libraries to map the substrate specificity of a peptide-modifying enzyme: A 13 residue consensus peptide specifies biotinylation in Escherichia coli. Biotechnology 11, 1138–1143 (1993)

    CAS  PubMed  Google Scholar 

  20. Knappik, A. & Pluckthun, A. An improved affinity tag based on the FLAG peptide for detection and purification of recombinant antibody fragments. Biotechniques 17, 754–761 (1994)

    CAS  PubMed  Google Scholar 

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We thank R. Rhinehart and K. Kenyon for technical assistance; H. Secrist, D. Byrd and R. Yeung for tissue materials; and S. Riddell for critically reading the manuscript. This work was supported by grants from the NIH.

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Correspondence to Veronika Groh.

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Groh, V., Wu, J., Yee, C. et al. Tumour-derived soluble MIC ligands impair expression of NKG2D and T-cell activation. Nature 419, 734–738 (2002).

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