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HLA-B2702 (77–83/83–77) Peptide Binds to ß-Tubulin on Human NK Cells and Blocks Their Cytotoxic Capacity¹

Raquel Tarazona^*, Guillermo López-Lluch^*, Maria-Dolores Galiani^*, Enrique Aguado^*, Fernando Barahona, Rafael Solana^* and José Peña^2,*

^* Department of Immunology, Faculty of Medicine, Hospital Reina Sofía, University of Córdoba, Córdoba, Spain; and Centro de Biología Molecular, University Autónoma of Madrid, Madrid, Spain

It has been described that peptides derived from a highly conserved region of the 1 helix of the first domain of HLA class I Ags exhibit immunomodulatory capacity blocking both T and NK cell cytotoxicity. In vivo treatment with these peptides prolongs survival of MHC-mismatched allografts. However, the molecular bases of these effects are still unclear. In this study, we further analyze the mechanisms by which the dimeric peptide HLA-B2702 (77–83/83–77) induces suppression of NK cell cytotoxicity. This peptide inhibits natural and redirected lysis mediated by NK cells without significantly affecting effector-target cell binding. We have also isolated and sequenced a protein that binds this inhibitory peptide, which structurally corresponds to ß-tubulin. Tubulin is the major protein of microtubules and is involved in target cell killing. Furthermore, B2702 peptide promotes GTP-independent tubulin assembly, producing aggregates that cannot be depolymerized by cold. Treatment of NK cells with Taxol or demecolcine, which interfere with microtubule organization, also prevents NK cell cytotoxicity. Taken together, these results support the hypothesis that the peptide B2702 (77–83/83–77) exerts its inhibitory effect on NK cell cytotoxicity by inducing polymerization of microtubules and interfering with their normal assembly/disassembly dynamics.

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