A retro-inverso peptide mimic of CD28 encompassing the MYPPPY motif adopts a polyproline type II helix and inhibits encephalitogenic T cells in vitro.
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.
Srinivasan
M
M
Department of Microbiology, College of Biological Sciences, Ohio State University, Columbus, OH 43210, USA.
Wardrop
R M
RM
Gienapp
I E
IE
Stuckman
S S
SS
Whitacre
C C
CC
Kaumaya
P T
PT
D020816:Amino Acid Motifs / Q000276:immunology; D000595:Amino Acid Sequence; D000818:Animals; D018106:CD28 Antigens / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000517:prevention & control; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D006168:Guinea Pigs; D007141:Immunoglobulin Fc Fragments / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018716:Molecular Mimicry / Q000276:immunology; D008969:Molecular Sequence Data; D004676:Myelin Basic Protein / Q000276:immunology; D010446:Peptide Fragments / Q000138:chemical synthesis* / Q000276:immunology / Q000494:pharmacology*; D010455:Peptides / Q000737:chemistry*; D011485:Protein Binding / Q000276:immunology; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012996:Solutions; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
D018106:CD28 Antigens; D018984:Epitopes, T-Lymphocyte; D007141:Immunoglobulin Fc Fragments; D007166:Immunosuppressive Agents; D004676:Myelin Basic Protein; D010446:Peptide Fragments; D010455:Peptides; D016693:Receptors, Antigen, T-Cell, alpha-beta; D011993:Recombinant Fusion Proteins; D012996:Solutions; C405722:myelin basic protein 1-11; C011083:polyproline