T-cell co-stimulatory pathways in autoimmunity.

T-cell activation and differentiation depend on the signal strength received by the T-cell receptor and on signals provided by co-stimulatory molecules. The most prominent co-stimulatory molecule is CD28, which controls the activation of naïve and memory T cells by antigen presented on professional antigen-presenting cells. Blocking of the CD28-CD80/86 pathway has been an appealing strategy for inducing tolerance in autoimmune diseases where the disease-inducing autoantigens are not known. Although CD28 has maintained its unique position, the past decade has witnessed the recognition that a large number of regulatory molecules on T cells must be stimulated to generate a fully protective immune response. These regulatory receptors differ in their preferential expression on T-cell subsets, in the ligands that they recognize, and in the signaling pathways that they trigger. They have in common the fact that they provide information on the cellular environment in which the T-cell response occurs. By intercepting these signals, we may be able to influence disease-relevant T-cell responses in autoimmune diseases while potentially minimizing broad immunosuppression.