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

Abstract

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.

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Acknowledgements

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). https://doi.org/10.1038/nature01112

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