Initiation of Signal Transduction through the T Cell Receptor Requires the Multivalent Engagement of Peptide/MHC Ligands

Abstract

While much is known about intracellular signaling events in T cells when T cell receptors (TCRs) are engaged, the mechanism by which signaling is initiated is unclear. We have constructed defined oligomers of soluble antigen-major histocompatibility complex (MHC) molecules, the natural ligands for the TCR. Using these to stimulate specific T cells in vitro, we find that agonist peptide/MHC ligands are nonstimulatory as monomers and minimally stimulatory as dimers. Similarly, a partial-agonist ligand is very weakly active as a tetramer. In contrast, trimeric or tetrameric agonist ligands that engage multiple TCRs for a sustained duration are potent stimuli. Ligand-driven formation of TCR clusters seems required for effective activation and helps to explain the specificity and sensitivity of T cells.

A Single-Chain Class II MHC-IgG3 Fusion Protein Inhibits Autoimmune Arthritis by Induction of Antigen-Specific Hyporesponsiveness

“…The degree of valence required for T cell signaling is still controversial. Triggering of T cells with anti-TCR mAb Fab has been reported (44); however, peptide/MHC ligands are nonstimulatory as monomers and optimal T cell activation requires trimeric or tetrameric ligands (45). Divalent TCR cross-linking has been demonstrated to induce T cell hyporesponsiveness in a number of studies (6 -10).…”

Synthetic Multivalent Ligands as Probes of Signal Transduction

“…[213] The four identical biotin-binding sites of biotin each bind with a dissociation constant of 10 -15 M; therefore, biotinylated recognition elements can be readily displayed from a streptavidin scaffold. Because streptavidin is tetravalent, multivalent complexes can be generated that present 1, 2, 3, or 4 recognition epitopes per scaffold (Figure 8).…”

“…Davis, McConnell, and coworkers developed streptavidin as a scaffold for the presentation of peptideloaded major histocompatibility complexes (MHCs). [213] Because peptide-loaded MHCs can serve as ligands for the TCR, streptavidin-bound biotinylated MHC complexes can bind (in principle) up to 4 TCRs.…”

TRAIL activates acid sphingomyelinase via a redox mechanism and releases ceramide to trigger apoptosis

“…Aggregation upon binding to the specific ligands has been reported for a large number of receptors including the TCR/CD3 complex (Boniface et al, 1998), BCR (Graziadei et al, 1990), CD40 (Vidalain et al, 2000), FceR1 (Field et al, 1995), CD95 (Schneider et al, 1998;Belka et al, 1999;Grassme et al, 2001b), CD28 (Viola et al, 1999), TNF-R , PDGFR (Liu et al, 1996) and CD2 (Rosenman et al, 1993). Ligandinduced receptor clustering results in a high local density of the receptor, trans-activation of receptor-associating signaling molecules and a local assembly of the signaling elements of the activated receptor, which facilitate transduction of extracellular signals into the cell.…”