Co-signal Molecules in T-Cell Activation : Historical Overview and Perspective

The two-signal model of T-cell activation, proposed approximately four decades ago, has undergone various refinements while maintaining its principal doctrine. Since the discovery of CD28, a variety of co-signal molecules, including co-stimulatory and co-inhibitory receptors and ligands, have been identified. These molecules fine-tune various immune responses both in the primary or secondary lymphoid tissues and in the peripheral tissues. Most co-signal receptors are expressed and induced on T cells during distinct stages (naïve/resting, activating, memory, and exhausting). These co-signaling pathways play critical and diverse roles in maintaining T-cell tolerance and eliciting T-cell immune responses in health and disease. This introductory chapter provides a historical overview of the key findings that have led to our current view of T-cell co-stimulation.