Abstract
The self-encoded ligands MICA (human) and Rae-1 (mouse) for the cytotoxic lymphocyte activating receptor NKG2D are highly expressed in carcinomas and inflammatory lesions and have been linked to immunosurveillance and graft rejection. However, whether NKG2D ligands have an intrinsic ability to acutely regulate tissue-associated immune compartments is not known. Here we show that epidermis-specific upregulation of Rae-1 induced rapid, coincident and reversible changes in the organization of tissue-resident Vγ5Vδ1 TCRγδ+ intraepithelial T cells and Langerhans cells, swiftly followed by epithelial infiltration by unconventional αβ T cells. Whereas local Vγ5Vδ1+ T cells limited carcinogenesis, Langerhans cells unexpectedly promoted it. These results provide unique insight into the early phases of tissue immunosurveillance and indicate that acute changes in NKG2D ligands may alone initiate a rapid, multifaceted immunosurveillance response in vivo.
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Acknowledgements
We thank R. Tigelaar, T. Silberzahn, J. Dyson, D. Oppenheim, M. Shlomchik and R. Montgomery for reagents, help and discussions. Supported by the National Cancer Institute (R01-CA102703 and P50-CA121974 to M.G.) and the Wellcome Trust (071534 to A.C.H. and J.S.).
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Supplementary Figures 1–5 and Supplementary Methods (PDF 1349 kb)
Supplementary Video 1
Interdigitating network of LC and DETC in resting murine epidermis. Three-dimensional analysis of the spatial relation between MHCII+ LC (green) and TCRγδ+ DETC (red) in the epidermis. Confocal microscopy image of epidermal sheet from wild-type FVB mouse was interpreted in 3D using Imaris software (Bitplane). (MOV 10861 kb)
Supplementary Video 2
Juxtaposed LC and DETC in the epidermis following local upregulation of Rae-1. Confocal microscopy image of epidermal sheet from a BiTg mouse after 72h on dox. MHCII+ LC (green); TCRγδ+ DETC (red). 3D rendering of confocal optical sections was prepared using Imaris software (Bitplane). (MOV 7211 kb)
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Strid, J., Roberts, S., Filler, R. et al. Acute upregulation of an NKG2D ligand promotes rapid reorganization of a local immune compartment with pleiotropic effects on carcinogenesis. Nat Immunol 9, 146–154 (2008). https://doi.org/10.1038/ni1556
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DOI: https://doi.org/10.1038/ni1556
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