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Inhibition of Cell Cycle Progression by a Synthetic Peptide Corresponding to Residues 65–79 of an HLA Class II Sequence: Functional Similarities but Mechanistic Differences with the Immunosuppressive Drug Rapamycin¹

Michelle L. Boytim^*, Shu-Chen Lyu^*, Ron Jung^*, Alan M. Krensky and Carol Clayberger^2,*,

^* Department of Cardiothoracic Surgery and Division of Immunology and Transplantation Biology/Department of Pediatrics, Stanford University, Stanford, CA 94305

A synthetic peptide corresponding to a region of the ₁ -helix of DQA03011 (DQ 65–79) inhibits the proliferation of human PBL and T cells in an allele-nonspecific manner. It blocks proliferation stimulated by anti-CD3 mAb, PHA-P, and alloantigen, but not by PMA and ionomycin. Substitution of each amino acid with serine shows that residues 66, 68, 69, 71–73, and 75–79 are critical for function. Inhibition of proliferation is long lasting and is not reversible with exogenous IL-2. The peptide can be added 24 to 48 h after stimulation and still block proliferation. The DQ 65–79 peptide does not affect expression of IL-2 or IL-2R; however, IL-2-stimulated proliferation is inhibited. Cell cycle progression is blocked at the G₁/S transition, and the activity of cdk2 (cyclin-dependent kinase 2) kinase is impaired by the continued presence of p27. Although these results suggest a mechanism similar to that of rapamycin, the peptide inhibition is not reversed with FK-506, which indicates a distinct mechanism.