D‐enantiomer peptide of the TCRa transmembrane domain inhibits T‐cell activation in vitro and in vivo

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Abstract
T cell activation requires the cross‐talk between the CD3‐signaling complex and the T cell receptor (TCR). A synthetic peptide coding for the TCRa 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.

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