T Cell Receptor (TCR) Signaling One of the first steps in the generation of the immune response is the recognition by T lymphocytes of peptide fragments (antigens) derived from foreign pathogens that are presented on the surface of antigen presenting cells (APC). This event is mediated by the T cell receptor (TCR), that transduces these extracellular signals by initiating a wide array of intracellular signaling pathways. One of the first biochemical events following TCR activation is the activation of Src family tyrosine kinases (p56lck) that, in turn, phosphorylate phospholipase Cγ1 (PLC). Activation of PLC leads to hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2), generating diacylglycerol (DAG) and inositol triphosphate (IP3). DAG activates protein kinase C (PKC) that, in turn, phorphorylates Ras, a GTPase that activates Raf leading to recruitment of the MAP kinase cascade. IP3 releases calcium from its intracellular stores in the endoplasmic reticulum (ER). The Ca2+ binds to calmodulin that, in turn, activates calcineurin, a Ca2+/calmodulin-dependent protein phosphatase. NFAT, a transcriptional regulator of interleukin-2 (IL-2) gene expression, is a direct target of calcineurin. Calcineurin dephosphorylates the cytosolic component of NFAT, NFATc, which migrates to the nucleus and induces transcription of the IL-2 gene.