Pathways

The T-cell receptor signalling pathway is an intracellular pathway that depicts how T-cells are activated as part of the cell-mediated immune response. T-cells are a type of lymphocyte produced by the thymus gland (T stands for thymus) that have a unique protein on their surface called the T-cell receptor. The T-cell receptor (TCR) is responsible for recognizing fragments of antigen as peptides bound to major histocompatibility complex (MHC) molecules (PMID: 6336315). T-cells are activated when they encounter another immune cell such as a dendritic cell or a B-cell that has digested a protein antigen and displayed the resulting peptide antigen fragments on their surface MHC molecules. These antigen-bound dendritic or B-cells are called antigen-presenting cells or APCs. The MHC-antigen complex from these APCs binds to the TCR of a given T-cell and then, through a series of signalling events (depicted in this pathway), the T-cell begins to secrete cytokines (PMID: 19132916). Some cytokines help the T-cell mature while other cytokines spur the growth of even more T-cells. The MHC-antigen-TCR binding event activates several signalling pathways such as the PI3K pathway that generates inositol triphosphate (IP3) at the plasma membrane. This leads to the recruitment of signalling molecules like PDK1 (pyruvate dehydrogenase kinase 1), PLC-gamma-1 (phospholipase C-gamma), diacylglycerol (DAG) and others that are essential for the activation of PKC-theta (protein kinase C-theta), and eventually the production of interleukin-2 (IL-2) as well as other cytokines (PMID: 19132916). As shown in this pathway the antigen is first presented to the T-cell receptor (consisting of an alpha and beta subunit) and the CD3 glycoprotein complex (PMID: 19132916). An early event in TCR activation is the phosphorylation of certain tyrosine containing motifs on the cytosolic side of the TCR/CD3 complex by a protein known as lymphocyte protein tyrosine kinase or Lck. After this phosphorylation event, a protein called the zeta-chain associated protein kinase (Zap-70) is recruited to the phosphorylated TCR/CD3 complex where it becomes activated (PMID: 7539035). This promotes the recruitment and phosphorylation of other proteins. For instance, the phosphorylation of SLP-76 by Zap-70 promotes the recruitment of a protein known as Vav (a guanine nucleotide exchange factor), as well as the adaptor proteins NCK and GADS, and an inducible T cell kinase known as Itk. Phosphorylation of PLC-gamma-1 by Itk results in the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) to produce the secondary messengers known as diacylglycerol (DAG) and inositol trisphosphate (IP3). DAG activates PKC-theta and the MAPK/Erk pathways, both promoting transcription factor NF-kappa-B activation. IP3 triggers the release of calcium from the endoplasmic reticulum, which promotes entry of extracellular Ca2+ into the T-cells where it is bound by calmodulin. Calcium-bound calmodulin (Ca2+/CaM) activates the phosphatase known as calcineurin (PMID: 22100452), which promotes IL-2 gene transcription through the transcription factor NFAT (Nuclear factor of activated T-cells) (PMID: 3260404).

The T-cell receptor signalling pathway is an intracellular pathway that depicts how T-cells are activated as part of the cell-mediated immune response. T-cells are a type of lymphocyte produced by the thymus gland (T stands for thymus) that have a unique protein on their surface called the T-cell receptor. The T-cell receptor (TCR) is responsible for recognizing fragments of antigen as peptides bound to major histocompatibility complex (MHC) molecules (PMID: 6336315). T-cells are activated when they encounter another immune cell such as a dendritic cell or a B-cell that has digested a protein antigen and displayed the resulting peptide antigen fragments on their surface MHC molecules. These antigen-bound dendritic or B-cells are called antigen-presenting cells or APCs. The MHC-antigen complex from these APCs binds to the TCR of a given T-cell and then, through a series of signalling events (depicted in this pathway), the T-cell begins to secrete cytokines (PMID: 19132916). Some cytokines help the T-cell mature while other cytokines spur the growth of even more T-cells. The MHC-antigen-TCR binding event activates several signalling pathways such as the PI3K pathway that generates inositol triphosphate (IP3) at the plasma membrane. This leads to the recruitment of signalling molecules like PDK1 (pyruvate dehydrogenase kinase 1), PLC-gamma-1 (phospholipase C-gamma), diacylglycerol (DAG) and others that are essential for the activation of PKC-theta (protein kinase C-theta), and eventually the production of interleukin-2 (IL-2) as well as other cytokines (PMID: 19132916). As shown in this pathway the antigen is first presented to the T-cell receptor (consisting of an alpha and beta subunit) and the CD3 glycoprotein complex (PMID: 19132916). An early event in TCR activation is the phosphorylation of certain tyrosine containing motifs on the cytosolic side of the TCR/CD3 complex by a protein known as lymphocyte protein tyrosine kinase or Lck. After this phosphorylation event, a protein called the zeta-chain associated protein kinase (Zap-70) is recruited to the phosphorylated TCR/CD3 complex where it becomes activated (PMID: 7539035). This promotes the recruitment and phosphorylation of other proteins. For instance, the phosphorylation of SLP-76 by Zap-70 promotes the recruitment of a protein known as Vav (a guanine nucleotide exchange factor), as well as the adaptor proteins NCK and GADS, and an inducible T cell kinase known as Itk. Phosphorylation of PLC-gamma-1 by Itk results in the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) to produce the secondary messengers known as diacylglycerol (DAG) and inositol trisphosphate (IP3). DAG activates PKC-theta and the MAPK/Erk pathways, both promoting transcription factor NF-kappa-B activation. IP3 triggers the release of calcium from the endoplasmic reticulum, which promotes entry of extracellular Ca2+ into the T-cells where it is bound by calmodulin. Calcium-bound calmodulin (Ca2+/CaM) activates the phosphatase known as calcineurin (PMID: 22100452), which promotes IL-2 gene transcription through the transcription factor NFAT (Nuclear factor of activated T-cells) (PMID: 3260404).

The T-cell receptor signalling pathway is an intracellular pathway that depicts how T-cells are activated as part of the cell-mediated immune response. T-cells are a type of lymphocyte produced by the thymus gland (T stands for thymus) that have a unique protein on their surface called the T-cell receptor. The T-cell receptor (TCR) is responsible for recognizing fragments of antigen as peptides bound to major histocompatibility complex (MHC) molecules (PMID: 6336315). T-cells are activated when they encounter another immune cell such as a dendritic cell or a B-cell that has digested a protein antigen and displayed the resulting peptide antigen fragments on their surface MHC molecules. These antigen-bound dendritic or B-cells are called antigen-presenting cells or APCs. The MHC-antigen complex from these APCs binds to the TCR of a given T-cell and then, through a series of signalling events (depicted in this pathway), the T-cell begins to secrete cytokines (PMID: 19132916). Some cytokines help the T-cell mature while other cytokines spur the growth of even more T-cells. The MHC-antigen-TCR binding event activates several signalling pathways such as the PI3K pathway that generates inositol triphosphate (IP3) at the plasma membrane. This leads to the recruitment of signalling molecules like PDK1 (pyruvate dehydrogenase kinase 1), PLC-gamma-1 (phospholipase C-gamma), diacylglycerol (DAG) and others that are essential for the activation of PKC-theta (protein kinase C-theta), and eventually the production of interleukin-2 (IL-2) as well as other cytokines (PMID: 19132916). As shown in this pathway the antigen is first presented to the T-cell receptor (consisting of an alpha and beta subunit) and the CD3 glycoprotein complex (PMID: 19132916). An early event in TCR activation is the phosphorylation of certain tyrosine containing motifs on the cytosolic side of the TCR/CD3 complex by a protein known as lymphocyte protein tyrosine kinase or Lck. After this phosphorylation event, a protein called the zeta-chain associated protein kinase (Zap-70) is recruited to the phosphorylated TCR/CD3 complex where it becomes activated (PMID: 7539035). This promotes the recruitment and phosphorylation of other proteins. For instance, the phosphorylation of SLP-76 by Zap-70 promotes the recruitment of a protein known as Vav (a guanine nucleotide exchange factor), as well as the adaptor proteins NCK and GADS, and an inducible T cell kinase known as Itk. Phosphorylation of PLC-gamma-1 by Itk results in the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) to produce the secondary messengers known as diacylglycerol (DAG) and inositol trisphosphate (IP3). DAG activates PKC-theta and the MAPK/Erk pathways, both promoting transcription factor NF-kappa-B activation. IP3 triggers the release of calcium from the endoplasmic reticulum, which promotes entry of extracellular Ca2+ into the T-cells where it is bound by calmodulin. Calcium-bound calmodulin (Ca2+/CaM) activates the phosphatase known as calcineurin (PMID: 22100452), which promotes IL-2 gene transcription through the transcription factor NFAT (Nuclear factor of activated T-cells) (PMID: 3260404).

The T helper cells (Th cells) are a type of T cell that play an important role in the immune system, particularly in the adaptive immune system. They help the activity of other immune cells by releasing T cell cytokines. These cells help suppress or regulate immune responses. They are essential in B cell antibody class switching, in the activation and growth of cytotoxic T cells, and in maximizing bactericidal activity of phagocytes such as macrophages.

proteins

Tacrine an anticholinesterase drug used primarily in the treatment of Alzheimer's disease, the drug also counters the effects of muscle relaxants, respiratory stimulants and other central nervous disorders. Its mechanism of action is not fully known but is thought that the drug reversibly binds and inhibits cholinesterase and acetylcholinesterase. Stopping the breakdown of acetylcholine leads to cholinergic receptors being further stimulated and accumulating in the synaptic cleft. Tacrine is a parasympathomimetic, meaning it acts as a cholinergic receptor stimulating agent that aids symptoms of mild to moderate dementia as seen in Alzheimer's. Symptoms of memory loss and deficiencies in cognitive function due to a loss of acetylcholine from the lack of cholinergic neurons within the brain. Tacrine should be taken on an empty stomach, at least one hour prior to a meal in order for optimal absorption to take place. It is metabolized by first-pass metabolism by the enzyme Cytochrome P450 1A2 resulting in velnacrine (1-hydroxy-tacrine). If an overdose does occur symptoms such as nausea, vomiting, salivation, sweating, bradycardia, hypotension, fainting and convulsions.

Metabolites of Tacrine are predicted with biotransformer.

Tacrolimus is a calcineurin inhibitor that is most often used as an immunosuppressive drug for organ transplant patients in order to reduce the activity of the immune system lowering the risk of organ rejection. Tacrolimus is administered orally or through a topical treatment which allows the drug to be absorbed into the bloodstream. Tacrolimus enters T-cells through the ABC or SLC transporters like ABCB1 and works by forming a complex with FKBP12 with inhibits calcineurin with leads to reduced T cell signal transduction and IL-2 transcription. IL-2 is an important mediator for T-cell activation, differentiation and migration which is through mTOR signalling. Lower IL-2 production and signal transduction leads to less activated immune cells leading to a weaker immune system. Tacrolimus also inhibits the transcription for genes encoding IL-3,4,5, GM-SCF, and TNF as well which are also involved in T cell activation. Organ transplant patients take tacrolimus after allogenic organ transplant for liver, kidney, heart, small bowel, pancreas, lung, trachea, skin, cornea and limb transplant.