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 synapse. Localization and segregation of signaling
molecules in and around the synapse are critical for initiation, propagation,
and termination of TCR signaling.

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 SHP1.

The Signal Triggering Module
consists primarily of the CD3 subunits in dimeric form, γε, δε, and ζζ, and the
Syk family kinase ZAP70. ZAP70 activates LAT leading to assembly of the LAT

The LAT Signalosome, or the
Signal Diversification and Regulation Module, is critical for the regulation of
TCR signaling. In the absence of proper LAT function, TCR signaling continues
unchecked resulting in antigen-independent proliferation of T cells, leading to
a disease known as LAT signaling pathology, an autoimmune lymphoproliferative
disorder. The LAT signalosome contains the key enzyme PLCγ1. PLCγ1
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 activation. 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 SOS.

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 NFκB pathway, and
activation of the RAS/MEK/ERK pathway, all leading to transcription of genes
involved in proliferation, cytokine production, and other effector functions. Ultimately
signaling is terminated primarily by dephosphorylation and inactivation of Lck.

In addition to CD4 and CD8, a
 number of important coreceptors are
known to influence T cell activation, each with its own signaling mechanism. 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 one more co-stimulatory
molecules such as CD28 and ICOS. Checkpoint immunotherapy uses antibodies
against negative regulatory ligands on tumor cells and APCs (e.g. PDL1) to
prevent T cells from being deactivated by contact with tumor cells.



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