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A Retro-Inverso Peptide Mimic of CD28 Encompassing the MYPPPY Motif Adopts a Polyproline Type II Helix and Inhibits Encephalitogenic T Cells In Vitro¹

Mythily Srinivasan^*, Richard M. Wardrop, Ingrid E. Gienapp, Scott S. Stuckman, Caroline C. Whitacre^, and Pravin T. P. Kaumaya^2,*,,

Departments of ^* Microbiology, College of Biological Sciences; Molecular Virology, Immunology, and Medical Genetics; Obstetrics and Gynecology, College of Medicine and Public Health; and Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210 response unit(s); MBP, myelin basic protein; CD, circular dichroism/dichroic; = mean residue molar ellipticity; SPR, surface plasmon resonance; L-CD28, CD28 free peptide; EL-CD28, end group-blocked CD28; RI-CD28, end group-blocked retro-inverso CD28; RL-CD28, end group-blocked reverse L CD28; D-CD28, end group-blocked D-CD28; LNC, lymph node cell(s).

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.

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				M. Srinivasan, D. Lu, R. Eri, D. D. Brand, A. Haque, and J. S. Blum CD80 Binding Polyproline Helical Peptide Inhibits T Cell Activation J. Biol. Chem., March 18, 2005; 280(11): 10149 - 10155. [Abstract] [Full Text] [PDF]

				M. Srinivasan, I. E. Gienapp, S. S. Stuckman, C. J. Rogers, S. D. Jewell, P. T. P. Kaumaya, and C. C. Whitacre Suppression of Experimental Autoimmune Encephalomyelitis Using Peptide Mimics of CD28 J. Immunol., August 15, 2002; 169(4): 2180 - 2188. [Abstract] [Full Text] [PDF]