Targeting the TCR: T-cell receptor and peptide-specific tolerance-based strategies for restoring self-tolerance in CNS autoimmune disease

A principal theme in autoimmunity is the breakdown of central tolerance resulting in the persistence and eventual activation of autoreactive T cells. Because CD4⁺ T cells are key contributors to the underlying pathogenic mechanisms responsible for the onset and progression of most autoimmune diseases, they are a logical target for therapeutic interventions. One technique for restoring self-tolerance is to exploit the endogenous regulatory mechanisms that govern CD4⁺ T-cell activation. In this review, we discuss promising techniques with the common goal of inducing antigen (Ag)-specific tolerance. Emphasis is given to the use of non-mitogenic anti-CD3 and peptide-specific tolerance strategies that specifically target the T-cell receptor (TCR) in the absence of costimulatory signals. These approaches produce a TCR signal of insufficient strength to cause CD4⁺ T-cell activation and instead induce functional T-cell anergy or deletion while avoiding generalized long-term immunosuppression.