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T Cell Recognition of an Engineered MHC Class I Molecule: Implications for Peptide-Independent Alloreactivity¹

Vladimir Jankovi^2,*,, Kristin Remus², Alberto Molano^2,3,, and Janko Nikolich-ugich^4,*,,

^* Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006; Laboratory of T Cell Development, Immunology Program, Memorial Sloan-Kettering Cancer Center, and Weill Graduate School of Medical Sciences, Cornell University, New York, NY 10021

Previously, we described H-2K^bW9 (K^bW9), an engineered variant of the murine MHC class I molecule H-2K^b (K^b), devoid of the central anchor ("C") pocket owing to a point mutation on the floor of the peptide binding site; this substitution drastically altered selection of bound peptides, such that the peptide repertoires of K^b and K^bW9 are largely nonoverlapping in vivo. On the basis of these observations, we used K^bW9 and K^b to revisit the role of peptides in alloreactive T cell recognition. We first compared Ab and TCR recognition of K^bW9 and K^b. Six of six K^b-specific mAbs, directed against different parts of the molecule, recognized K^bW9 well, albeit at different levels than K^b. Furthermore, K^bW9 readily served as a restriction element for a peptide-specific syngeneic CTL response. Therefore, K^bW9 mutation did not result in gross distortions of the TCR-interacting surface of class I, which was comparable between K^b and K^bW9. Interestingly, when K^bW9 was used to stimulate allogeneic T cells, it induced an infrequent CTL population that cross-reacted against K^b and was specific for peptide-independent MHC epitopes. By contrast, K^b-induced alloreactive CTLs recognized K^b in a peptide-specific manner, did not cross-react on K^bW9, and were present at much higher frequencies than those induced by K^bW9. Thus, induction of rare peptide-independent CTLs depended on unique structural features of K^bW9, likely due to the elevated floor of the peptide-binding groove and the consequent protruding position of the peptide. These results shed new light on the relationship between TCR and peptide-MHC complex in peptide-independent allorecognition.

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