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

David E Oppenheim¹, Scott J Roberts², Sarah L Clarke¹, Renata Filler², Julie M Lewis², Robert E Tigelaar², Michael Girardi² & Adrian C Hayday¹

¹  Peter Gorer Department of Immunobiology, Guy's King's St. Thomas' School of Medicine, King's College, Guy's Hospital Campus, London SE1 9RT, UK.

²  Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut 06511, USA.

Upregulation of the inducible gene products MICA (human) and Rae-1 (mouse) may promote tumor surveillance and autoimmunity by engaging the activating receptor NKG2D on natural killer (NK) cells and T cells. Nevertheless, sustained expression of MICA by tumors can also elicit NKG2D downregulation, perhaps indicating 'immunoevasion'. Investigating this paradox, we report here that constitutive Rae-1 transgene expression in normal epithelium elicited local and systemic NKG2D downregulation, generalized but reversible defects in NK cell−mediated cytotoxicity and mild CD8⁺ T cell defects. The extent of NKG2D downregulation correlated well with the incidence and progression of cutaneous carcinogenesis, emphasizing the utility of NKG2D as a marker of tumor resistance. Thus, NKG2D engagement is a natural mediator of immunosurveillance, which can be compromised by locally sustained ligand expression but potentially restored by innate immune activation.

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