Naïve cytotoxic CD8+ T cells scan the cell surface of antigen-presenting cells (APCs), such as dendritic cells (DCs), which present processed peptides on MHC molecules. The inputs from T cell receptors (TCRs) function as signal 1, those from costimulatory molecules (such as CD28, OX40, and ICOS) act as signal 2, and cytokines (such as IL-12) provide signal 3; these signals are combined to generate appropriate intracellular signaling events that dictate the outcome of T cell fate. Recognition of cognate foreign antigens with appropriate signals 2 and 3 activates CD8+ T cells to differentiate into effector T cells. CD8+ T cells responding to self-antigens are subjected to peripheral tolerance, in which they are either deleted by apoptosis or inactivated (or suppressed) by regulatory T cells (Tregs). Insufficient signals 2 and 3 or strong negative signals provided by coinhibitory molecules (such as PD1 and CTLA4) result in incomplete activation of T cells, which are then called anergic T cells. Persistent cognate antigen stimulation during chronic infection or cancer induces another hyporesponsive state of T cells called exhaustion, which is characterized by high expression of multiple coinhibitory molecules.