TCR Signaling
The T-Cell Receptor (TCR) is a protein complex on the surface of T-cells responsible for the recognition of antigens on the surface of antigen presenting cells (APC). Cell surface glycoproteins CD4 and CD8 serve as coreceptors with the TCR primarily for the interaction with the major histocompatibility complex class II (MHC II) loaded with peptides derived from cytosolic proteins and MHC I with extracellular protein peptides respectively. Activation of the TCR induces a number of signaling cascades, ultimately leading to the transcription of several gene products essential for T cells differentiation, proliferation and secretion of a number of cytokines.
CD45 regulated activation of Src-family kinases LCK and FYN leads to phosphorylation of TCR immunoreceptor tyrosine-based activation motifs (ITAMs) in CD3, creating a docking site for ZAP-70. Phosphorylation and activation is modulated by CD45. ZAP-70 binds to the CD3 zeta chain, which positions the protein kinase to phosphorylate the transmembrane protein linker of activated T cells (LAT). Signaling proteins like SLP-76 can now dock to LAT and are also phosphorylated by ZAP-70. SLP-76 promotes recruitment of Vav, the adaptor proteins NCK and GRAP2, and an inducible T cell kinase (Itk).
Further recruitment of other protein upon LAT and SLP-76 phosphorylation leads to calcium mobilization, Ras Activation and cytoskeletal reorganization. Phosphorylation of phospholipase C γ1 (PLCγ1) by the Itk results in the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) to produce the second messenger inositol trisphosphate (IP3) and diacylglycerol (DAG). DAG activates PKC4 and the MAPK/Erk pathways cascade which leads to activation of transcription factor NF-κB and ATF2 activation and relocation into nucleus. IP3 promotes release of Ca2+ from the ER, which triggers entry of extracellular Ca2+ into cells through calcium release-activated Ca2+ (CRAC) channels. Calcium-bound calmodulin (Ca2+/CaM) activates the phosphatase calcineurin. Transcription factor NFAT gets activated and promotes IL-2 gene transcription.
TCR signaling is regulated on several levels to diversify the cell response. Extracellular signals are recognized by additional cell surface receptors like CD28 or LFA-1 and modulate cellular response further. Besides, tight negative regulation is essential to prevent hyperactivation of the pathway and the associated immune response.
Aberrant TCR signaling can lead to immune dysregulation, contributing to conditions such as multiple sclerosis, rheumatoid arthritis, and type 1 diabetes. In oncology, modulating TCR signaling is central to adoptive T-cell therapies, including chimeric antigen receptor (CAR) T-cell therapy and engineered TCR-T cells, which enhance antigen recognition and tumor clearance. Furthermore, checkpoint inhibitors targeting molecules downstream of TCR activation, such as CTLA-4 and PD-1, have revolutionized cancer treatment by reinvigorating exhausted T cells. Current research continues to explore ways to fine-tune TCR signaling, aiming to develop more precise immunotherapies with reduced toxicity, as well as novel strategies to restore immune homeostasis in autoimmune disorders. These advances underscore the clinical relevance of TCR signaling and its potential as a therapeutic target in diverse disease settings.
Related Pathways and Resources
- Human Leukocyte Antigen
- Autoimmune Diseases
- Multiple Sclerosis
- Rheumatoid Arthritis
- Hallmarks of Cancer
- Cancer Immune Checkpoints
- CAR-T Immunotherapy Research
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