A retro-inverso peptide mimic of CD28 encompassing the MYPPPY motif adopts a polyproline type II helix and inhibits encephalitogenic T cells in vitro

J Immunol. 2001 Jul 1;167(1):578-85. doi: 10.4049/jimmunol.167.1.578.

Abstract

Complete activation of T cells requires two signals: an Ag-specific signal delivered via the TCR by the peptide-MHC complex and a second costimulatory signal largely provided by B7:CD28/CTLA-4 interactions. Previous studies have shown that B7 blockade can either ameliorate experimental autoimmune encephalomyelitis by interfering with CD28 signaling or exacerbate the disease by concomitant blockade of CTLA-4 interaction. Therefore, we developed a functional CD28 mimic to selectively block B7:CD28 interactions. The design, synthesis, and structural and functional properties of the CD28 free peptide, the end group-blocked CD28 peptide, and its retro-inverso isomer are shown. The synthetic T cell-costimulatory receptor peptides fold into a polyproline type II helical structure commonly seen in regions of globular proteins involved in transient protein-protein interactions. The binding determinants of CD28 can be transferred onto a short peptide mimic of its ligand-binding region. The CD28 peptide mimics effectively block the expansion of encephalitogenic T cells in vitro suggesting the potential usefulness of the peptides for the treatment of autoimmune disease conditions requiring down-regulation of T cell responses.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Motifs / immunology
  • Amino Acid Sequence
  • Animals
  • CD28 Antigens / chemistry*
  • CD28 Antigens / metabolism
  • CD28 Antigens / physiology*
  • Cells, Cultured
  • Encephalomyelitis, Autoimmune, Experimental / immunology*
  • Encephalomyelitis, Autoimmune, Experimental / prevention & control
  • Epitopes, T-Lymphocyte / immunology
  • Female
  • Guinea Pigs
  • Immunoglobulin Fc Fragments / metabolism
  • Immunosuppressive Agents / chemical synthesis
  • Immunosuppressive Agents / pharmacology*
  • Lymphocyte Activation / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Molecular Mimicry / immunology
  • Molecular Sequence Data
  • Myelin Basic Protein / immunology
  • Peptide Fragments / chemical synthesis*
  • Peptide Fragments / immunology
  • Peptide Fragments / pharmacology*
  • Peptides / chemistry*
  • Protein Binding / immunology
  • Protein Conformation
  • Protein Structure, Secondary
  • Receptors, Antigen, T-Cell, alpha-beta / genetics
  • Recombinant Fusion Proteins / metabolism
  • Solutions
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism

Substances

  • CD28 Antigens
  • Epitopes, T-Lymphocyte
  • Immunoglobulin Fc Fragments
  • Immunosuppressive Agents
  • Myelin Basic Protein
  • Peptide Fragments
  • Peptides
  • Receptors, Antigen, T-Cell, alpha-beta
  • Recombinant Fusion Proteins
  • Solutions
  • myelin basic protein 1-11
  • polyproline