Activation of helper T cell has been implicated in a number of autoimmune diseases including rheumatoid arthritis. The underlying mechanism that initiates and promotes disease progression remains unclear, but it is apparent that helper T cells and autoantigens play prominent roles. Identification of the autoantigens has proven to be extremely difficult, and therefore strategies for promoting tolerance induction remain limited. Since autoimmune diseases are closely associated with specific major histocompatibility complex class II molecules such as HLA-DR4, the use of competitor peptides is an alternative strategy. A limitation of competitor peptides, however, is that they are ineffective in vivo. In the studies presented here, we demonstrate that coupling competitor peptides to a cell-surface receptor ligand, transferrin, enhances their ability to block helper T cell responses using the DO11.10 transgenic mouse as our model system.