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Costimulation of CD8αβ T cells by NKG2D via engagement by MIC induced on virus-infected cells

Nature Immunology volume 2, pages 255–260 (2001)Cite this article

Abstract

NKG2D is an activating receptor that stimulates innate immune responses by natural killer cells upon engagement by MIC ligands, which are induced by cellular stress. Because NKG2D is also present on most CD8αβ T cells, it may modulate antigen-specific T cell responses, depending on whether MIC molecules—distant homologs of major histocompatibility complex (MHC) class I with no function in antigen presentation—are induced on the surface of pathogen-infected cells. We found that infection by cytomegalovirus (CMV) resulted in substantial increases in MIC on cultured fibroblast and endothelial cells and was associated with induced MIC expression in interstitial pneumonia. MIC engagement of NKG2D potently augmented T cell antigen receptor (TCR)-dependent cytolytic and cytokine responses by CMV-specific CD28− CD8αβ T cells. This function overcame viral interference with MHC class I antigen presentation. Combined triggering of TCR-CD3 complexes and NKG2D induced interleukin 2 production and T cell proliferation. Thus NKG2D functioned as a costimulatory receptor that can substitute for CD28.

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Figure 1: Induction of MIC expression on CMV-infected fibroblasts and endothelial cells.
Figure 2: Association of induced MIC expression with productive CMV infection in cultured endothelial cells and lung disease.
Figure 3: Augmentation of anti-CMV cytolytic T cell responses by MICA-NKG2D.
Figure 4: Antigen dose-dependent augmentation of cytolytic T cell function by NKG2D.
Figure 5: Stimulation of T cell cytokine secretion by NKG2D.
Figure 6: Stimulation by NKG2D of IL-2 production in peripheral blood CMV-specific CD28− CD8αβ T cells.
Figure 7: Costimulation by NKG2D of TCR-CD3 complex–dependent IL-2 production and proliferation of CD28− CD8αβ T cells

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Acknowledgements

We thank L. De Jong for assistance; C. Yee for helpful discussions; D. Myerson for tissue specimens; and M. Lopez-Botet and L. Lanier for antibodies. J. R.-H. thanks B. Torok-Storb for support through National Institutes of Health (NIH) grant CA18221. Supported by a Cancer Research Institute Junior Council Fellowship (to M. S. T.) and NIH grants CA18029 and AI41754 (to S. R. R.) and CA18221 and AI30581 (to T. S.).

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  1. Rebecca Rhinehart and Julie Randolph-Habecker: These authors contributed equally to this work.

Authors and Affiliations

  1. Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. North, Seattle, 98109, WA, USA

    Veronika Groh, Max S. Topp, Stanley R. Riddell & Thomas Spies

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Correspondence to Veronika Groh or Thomas Spies.

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Groh, V., Rhinehart, R., Randolph-Habecker, J. et al. Costimulation of CD8αβ T cells by NKG2D via engagement by MIC induced on virus-infected cells. Nat Immunol 2, 255–260 (2001). https://doi.org/10.1038/85321

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