Potent T cell activation with dimeric peptide-major histocompatibility complex class II ligand: The role of CD4 coreceptor

Abstract

The interaction of the T cell receptor (TCR) with its cognate peptide- major histocompatibility complex (MHC) on the surface of antigen presenting cells (APCs) is a primary event during T cell activation. Here we used a dimeric IE(k)-MCC molecule to study its capacity to activate antigen-specific T cells and to directly analyze the role of CD4 in physically stabilizing the TCR-MHC interaction. Dimeric IE(k)-MCC stably binds to specific T cells. In addition, immobilized dimeric IE(k)-MCC can induce TCR downregulation and activate antigen-specific T cells more efficiently than anti-CD3. The potency of the dimeric IE(k)-MCC is significantly enhanced in the presence of CD4. However, CD4 does not play any significant role in stabilizing peptide-MHC- TCR interactions as it fails to enhance binding of IE(k)-MCC to specific T cells or influence peptide-MHC-TCR dissociation rate or TCR downregulation. Moreover, these results indicate that dimerization of peptide-MHC class II using an IgG molecular scaffold significantly increases its binding avidity leading to an enhancement of its stimulatory capacity while maintaining the physiological properties of cognate peptide-MHC complex. These peptide-MHC- IgG chimeras may, therefore, provide a novel approach to modulate antigen- specific T cell responses both in vitro and in vivo.