POTENT T-CELL ACTIVATION WITH DIMERIC PEPTIDE MAJOR HISTOCOMPATIBILITY COMPLEX CLASS-II LIGAND - THE ROLE OF CD4 CORECEPTOR

The interaction of the T cell receptor (TCR) with its cognate peptide- major histocompatibility complex (MHC) on the surface of antigen prese nting cells (APCs) is a primary event during T cell activation. Here w e used a dimeric IEk-MCC molecule to study its capacity to activate an tigen-specific T cells and to directly analyze the role of CD4 in phys ically stabilizing the TCR-MHC interaction. Dimeric IEk-MCC stably bin ds to specific T cells. In addition, immobilized dimeric IEk-MCC can i nduce TCR downregulation and activate antigen-specific T cells more ef ficiently than anti-CDS. The potency of the dimeric IEk-MCC is signifi cantly enhanced in the presence of CD4. However, CD4 does not play any significant role in stabilizing peptide-MHC-TCR interactions as it fa ils to enhance binding of IEk-MCC to specific T cells or influence pep tide-MHC-TCR dissociation rate or TCR downregulation. Moreover, these results indicate that dimerization of peptide-MHC class II using an Ig G molecular scaffold significantly increases its binding avidity leadi ng to an enhancement of its stimulatory capacity while maintaining the physiological properties of cognate peptide-MHC complex. These peptid e-MHC-IgG chimeras may, therefore, provide a novel approach to modulat e antigen-specific T cell responses both in vitro and in vivo.