TCR signaling. T-cell activation is initiated by the interaction of TCR with peptide-MHC and coreceptors (ie, CD4 or CD8) and other costimulatory molecules including CD28, resulting in the multimolecular signalosomes, followed by the activation of several distal signaling pathways such as Ca2+-calcineurin-NFATs, PKCθ–IKK–NF-κβ, RASGRP1-RAS-ERK1/2, and TSC1/2-mTOR. The signaling complex containing scaffold adapter molecules, SLP-76 and GADs, which recruits PLCγ1 and tyrosine kinase ITKs. The tyrosine kinase ITK phosphorylates and activates PLCγ1, which then cleaves phosphatidylinositol (4,5) bisphosphate to generate 2 important second messengers, IP3 and DAG. IP3 binds to receptors on the ER, leading to an initial phase of calcium release, which subsequently activates the NFAT family of TFs, whose targets include many important cytokines, including IL-2 that are activated. Upon TCR activation, IL-2 receptor (IL-2R) activates JAK3, which in turn phosphorylates the beta-chain of IL-2R, recruiting JAK1. Both JAK1 and JAK3 in their active form phosphorylates (STAT), resulting in the nucleus transport. DAG activates several important proteins including several isoforms of PKC and RASGRP1 and RASGRP2, that are responsible for an initial phase of RAS activation, which is then sustained and amplified by SOS1. PKCθ binds to DAG and is recruited to the lipid rafts and triggers the formation of a trimolecular complex of adapter proteins in the cytoplasm called the CBM complex (CARMA1, BCL10, and MALT1), resulting in PKCθ–IKKβ–NF-κβ pathway activation. DAG induces the activation of another key molecule, RASGRP1, responsible for RAS activation in T cells, and initiates the RAS-MAPK cascade by activating the serine/threonine kinase Raf1 and activates MAPK ERK1 and 2. The costimulatory molecules CD28 mediates PI3K and VAV1 activation and further increases NF-κB and NFAT nuclear translocation, augmenting T-cell survival and production of the proliferative cytokine IL-2. Other TFs or pathways (p38MAPK, ERK1/2, and STAT3) are also crucial for T-cell activation and distinct functions associated with T cells. Several key genes involved in TCR are either genetically aberrant (highlighted in yellow text) or indirectly affected by other alterations in several PTCL subtypes as indicated below. Pathways that are relevant to PTCL entities are highlighted by brackets, followed by the PTCL entity in which the pathway is implicated in. CARMA1, caspase recruitment domain–containing membrane–associated guanylate kinase protein 1; DAG, diacylglycerol; ER, endoplasmic reticulum; ERK, extracellular signal–regulated kinase; IP3, inosine trisphosphate; MALT1, mucosa-associated lymphoid tissue translocation protein 1; mTOR, mammalian target of rapamycin; NFAT, nuclear factor of activated T cell; PKCθ, protein kinase C θ; PLCγ1, phospholipase Cγ1; RASGRP1, RAS guanyl nucleotide–releasing protein 1.
