D-enantiomer peptide of the TCRalpha transmembrane domain inhibits T-cell activation in vitro and in vivo.
T cell activation requires the cross-talk between the CD3-signaling complex and the T cell receptor (TCR). A synthetic peptide coding for the TCRalpha transmembrane domain (CP) binds CD3 molecules, interferes with the CD3/TCR cross-talk, and inhibits T cell activation. Intermolecular interactions are sterically constrained; accordingly no sequence-specific interactions are thought to occur between D- and L-stereoisomers. This argument was recently challenged when applied to intra-membrane protein assembly. In this paper we studied the ability of a D-stereoisomer of CP (D-CP) to inhibit T cell activation. L-CP and D-CP co-localized with the TCR in the membrane and inhibited T cell activation in a sequence-specific manner. In vivo, both L-CP and D-CP inhibited adjuvant arthritis. In molecular terms, these results suggest the occurrence of structural reorientation that facilitates native-like interactions between D-CP and CD3 within the membrane. In clinical terms, our results demonstrate that D-stereoisomers retain the therapeutic properties of their L-stereoisomers, while they benefit from an increased resistance to degradation.
Gerber
Doron
D
Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot, Israel.
Quintana
Francisco J
FJ
Bloch
Itai
I
Cohen
Irun R
IR
Shai
Yechiel
Y
D000818:Animals; D005260:Female; D006968:Hypersensitivity, Delayed / Q000517:prevention & control; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D007249:Inflammation / Q000517:prevention & control; D008213:Lymphocyte Activation; D010446:Peptide Fragments / Q000032:analysis / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D051381:Rats; D011917:Rats, Inbred Lew; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000737:chemistry / Q000502:physiology*; D013237:Stereoisomerism; D013601:T-Lymphocytes / Q000276:immunology*
D007166:Immunosuppressive Agents; D010446:Peptide Fragments; D016693:Receptors, Antigen, T-Cell, alpha-beta