In summary, in our in vivo model, exhibiting a constitutive NKG2DL expression and a consecutive persistent NKG2DL-induced NKG2D downregulation as it is observed in tumor patients, we could neither detect a functional impairment of the activating receptor NKp46 nor a marked CD3ζ downregulation even upon enforced chronic NKG2D engagement. Here, KLRK1 is linked to neoplasm.