title: A human class II MHC-derived peptide antagonizes phosphatidylinositol 3-kinase to block IL-2 signaling.
abstract: MHC molecules bind antigenic peptides and present them to T cells. There is a growing body of evidence that MHC molecules also serve other functions. We and others have described synthetic peptides derived from regions of MHC molecules that inhibit T-cell proliferation or cytotoxicity in an allele-nonspecific manner that is independent of interaction with the T-cell receptor. In this report, we describe the mechanism of action of a synthetic MHC class II-derived peptide that blocks T-cell activation induced by IL-2. Both this peptide, corresponding to residues 65-79 of DQA*03011 (DQ 65-79), and rapamycin inhibit p70 S6 kinase activity, but only DQ 65-79 blocks Akt kinase activity, placing the effects of DQ 65-79 upstream of mTOR, a PI kinase family member. DQ 65-79, but not rapamycin, inhibits phosphatidylinositol 3-kinase (PI 3-kinase) activity in vitro. The peptide is taken up by cells, as demonstrated by confocal microscopy. These findings indicate that DQ 65-79 acts as an antagonist with PI 3-kinase, repressing downstream signaling events and inhibiting proliferation. Understanding the mechanism of action of immunomodulatory peptides may provide new insights into T-cell activation and allow the development of novel immunosuppressive agents.
authors.affiliation: Program in Immunology, Division of Immunology and Transplantation Biology, Department of Pediatrics, Stanford University, Stanford, California 94305-5407, USA.
authors.forename: M L
authors.initials: ML
authors.lastname: Boytim
authors.forename: P
authors.initials: P
authors.lastname: Lilly
authors.forename: K
authors.initials: K
authors.lastname: Drouvalakis
authors.forename: S C
authors.initials: SC
authors.lastname: Lyu
authors.forename: R
authors.initials: R
authors.lastname: Jung
authors.forename: A M
authors.initials: AM
authors.lastname: Krensky
authors.forename: C
authors.initials: C
authors.lastname: Clayberger
mesh_terms: D000595:Amino Acid Sequence; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D000949:Histocompatibility Antigens Class II / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism*; D008213:Lymphocyte Activation; D008954:Models, Biological; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000037:antagonists & inhibitors; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
chemical_list: D000949:Histocompatibility Antigens Class II; D007376:Interleukin-2; D010446:Peptide Fragments; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015375:Receptors, Interleukin-2; D014443:Tyrosine; D019893:Ribosomal Protein S6 Kinases