NKG2D ligands and a timely response to alteration in their expression by epidermal γδTCR+ intraepithelial lymphocytes (IELs). (A) Human and mouse NKG2D ligands, their cell surface anchor and their affinity to NKG2D are shown. (B) Representative confocal images of murine epidermal Vγ5Vδ1+ lELs in whole epidermal sheets following transgenic upregulation of Rae-1 under the involucrin promoter. (i) Single-transgenic and (ii) bi-transgenic mice were fed with doxycycline for 72 h, inducing expression of Rae-1 only in bi-transgenic mice (4). (iii) Mice with sustained expression of Rae-1 under the involucrin promoter (19). The images depict how acute expression of Rae-1 on epithelial cells induces morphological and activational changes in the neighboring IELs, whereas constitutive expression of Rae-l renders them hyporesponsive. Abbreviations: *allele-dependent NKG2D, natural killer group 2 member D; MIC, MHC class I-chain-related protein; ULBP, cytomegalovirus UL16-binding protein; Rae-1, retinoic acid early-inducible 1; MULT1, murine UL16-binding protein-like transcript 1; al, a2, and a3, analogous to the a1, a2, and a3 domains of MHC 1a proteins; TM, transmembrane protein; GPl, glycosylphosphatidylinositol-linked protein; ND, not determined.