T cell receptor signaling pathway

Definition

Target type: biologicalprocess

The series of molecular signals initiated by the cross-linking of an antigen receptor on a T cell. [GOC:add]

The T cell receptor (TCR) signaling pathway is a complex cascade of events that begins with the recognition of antigen presented by antigen-presenting cells (APCs) and culminates in the activation of T lymphocytes. This pathway is crucial for the adaptive immune response, enabling T cells to mount specific responses to a wide range of pathogens and other foreign antigens.

The pathway is initiated when the TCR, a heterodimer composed of α and β chains, binds to a peptide-MHC complex displayed on the surface of an APC. This interaction triggers a series of intracellular signaling events that involve a network of proteins and enzymes. Key components of the TCR signaling pathway include:

- **The TCR complex:** This complex consists of the TCR αβ heterodimer, CD3 proteins (CD3ε, CD3γ, and CD3δ), and ζ chains. CD3 and ζ chains function as signal transduction modules, transmitting the signal from the TCR to downstream signaling pathways.

- **Lck:** This tyrosine kinase is associated with the CD4 or CD8 coreceptors on T cells. Upon TCR engagement, Lck is activated and phosphorylates ITAMs (immunoreceptor tyrosine-based activation motifs) in the cytoplasmic tails of CD3 and ζ chains.

- **Zap70:** This tyrosine kinase is recruited to the phosphorylated ITAMs of CD3 and ζ chains. Zap70 is then activated and phosphorylates a number of downstream signaling molecules, including LAT (linker for activation of T cells) and PLCγ1 (phospholipase C-gamma 1).

- **LAT and PLCγ1:** These proteins play critical roles in the downstream signaling cascade. LAT acts as a scaffolding protein, recruiting a variety of signaling molecules to the TCR complex, while PLCγ1 hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) into diacylglycerol (DAG) and inositol trisphosphate (IP3).

- **Calcium signaling:** IP3 diffuses into the cytoplasm and binds to receptors on the endoplasmic reticulum, causing the release of calcium ions (Ca2+). Increased intracellular calcium levels activate calcineurin, a phosphatase that dephosphorylates NFAT (nuclear factor of activated T cells).

- **MAPK pathway:** DAG activates protein kinase C (PKC), which in turn activates the mitogen-activated protein kinase (MAPK) pathway. The MAPK pathway leads to the phosphorylation and activation of transcription factors, including AP-1 (activator protein-1).

- **NFAT and AP-1:** These transcription factors translocate to the nucleus and activate the expression of genes involved in T cell activation, proliferation, and differentiation. These genes include cytokines, chemokines, and cell surface receptors that contribute to the immune response.

The TCR signaling pathway is tightly regulated, with multiple mechanisms in place to ensure that T cells are only activated when appropriate. These mechanisms include:

- **Negative regulators:** Several proteins act as negative regulators of the TCR signaling pathway, including phosphatases, ubiquitin ligases, and inhibitory receptors.

- **Threshold of activation:** The strength of the TCR signal is critical for T cell activation. Weak signals may not be sufficient to activate the pathway, while strong signals can lead to sustained activation and potentially harmful immune responses.

- **Anergy:** T cells that encounter antigens without appropriate costimulatory signals can become anergic, a state of unresponsiveness.

The TCR signaling pathway is a complex and highly regulated process that plays a critical role in the immune response. Dysregulation of this pathway can lead to various immune disorders, including autoimmune diseases and immunodeficiency. Understanding the details of this pathway is essential for developing effective therapies for these conditions.'
"

Proteins (48)

Compounds (746)