T cell receptor (TCR) signaling is initiated by engagement of TCRs with MHC-peptide complexes on the surface of antigen presenting cells (APCs). The area of contact between a T cell and APC is called the immunological synapse3,4. Localization and segregation of signaling molecules in and around the synapse are critical for initiation, propagation, and termination of TCR signaling3,4.
The TCR signaling apparatus can be divided into three different modules: the SFK Regulation Module, the Signal Triggering Module, and the Signal Diversification and Regulation Module (the LAT signalosome)1.
The SFK Regulation Module contains the tyrosine kinase p56Lck (Lck) which is bound to the cytoplasmic tails of the CD4/8 co-receptor molecules. The coreceptors interact with the MHC molecules on APCs, stabilizing the binding of the TCR, and also bringing Lck into proximity with the TCR Signal Triggering Module. The SFK Regulation Module also includes a number of phosphatases that regulate the activation state of Lck, including CD45, CSK, PTPN22, and SHP11,3.
The Signal Triggering Module consists primarily of the CD3 subunits in dimeric form, ge, de, and zz, and the Syk family kinase ZAP701. ZAP70 activates LAT leading to assembly of the LAT signalosome1,3,6.
The LAT Signalosome, or the Signal Diversification and Regulation Module, is critical for the regulation of TCR signaling1. In the absence of proper LAT function, TCR signaling continues unchecked resulting in antigen-independent proliferation of T cells2,3,7, leading to a disease known as LAT signaling pathology, an autoimmune lymphoproliferative disorder. The LAT signalosome contains the key enzyme PLCg1. PLCg1 cleaves the lipid messenger PIP2 into DAG and IP3 resulting in the downstream activation of PKC and the release of calcium from the ER, both important for downstream signaling events and transcriptional activation1,2,3,6,7. The LAT signalosome contains a number of other kinases and adapter proteins important for propagating the TCR signal including SLP76, ITK, Vav1, GADS, GRB2, RAC1, and SOS1,2,3,6,7.
During TCR signaling, binding of the TCR activates Lck. Activated Lck then phosphorylates ITAM domains in the cytoplasmic tails of the CD3 subunits, and ZAP70. Phosphorylated ZAP70 then recruits and phosphorylates LAT causing the assembly of the LAT signalosome. Together these events set off a complex and tightly regulated sequence of events including the calcium-dependent activation and translocation of NFAT, activation of the NFkB pathway, and activation of the RAS/MEK/ERK pathway, all leading to transcription of genes involved in proliferation, cytokine production, and other effector functions1,3,6.
In addition to CD4 and CD8, a number of important coreceptors are known to influence T cell activation, each with its own signaling mechanism5. For example CD28, ICOS, and CD40L augment T cell activation by lowering the TCR signaling threshold. Another group, including PD1 and CTLA4, act as negative regulators of T cell activation. Many of these molecules have become the focus of cancer immunotherapies. CAR T cells are triggered by artificial TCRs consisting of an external tumor-specific targeting domain coupled to a cytoplasmic tail composed of the signaling moieties of CD3 and one or more co-stimulatory molecules such as CD28 and ICOS5. Checkpoint immunotherapy uses antibodies against negative regulatory ligands on tumor cells and APCs (e.g. PD-L1) to prevent T cells from being deactivated by contact with tumor cells8.
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Key Elements in TCR Signaling. T cell receptor (TCR) signaling is initiated by engagement of TCRs with MHC-peptide complexes on the surface of antigen presenting cells (APCs). The core TCR signaling complex consists of the CD3 subunits in dimeric form, ge, de, and zz, and the Syk family kinase ZAP70. During TCR signaling binding of the TCR activates Lck, which then phosphorylates the cytoplasmic tails of the CD3 subunits and ZAP70. ZAP70 phosphorylates LAT causing the assembly of the LAT signalosome. PLCg1 cleaves PIP2 into DAG and IP3 resulting in the activation of PKC and the release of calcium from the ER, both important for downstream signaling events and transcriptional activation. Together these events set off a complex and tightly regulated signaling cascade leading to transcription of genes involved in proliferation, cytokine production, and other effector functions.
Below is the entire list of targets involved with TCR Signaling: