The Introduction of TCR Signaling Pathways

  • T-cell-related immunotherapy has shown great promise in recent cancer research. The main force is CAR-T and TCR-T technologies. Compared with CAR-T cell therapy, TCR-T therapy attracts less attention, but both of them belong to the frontier gene therapy for cancer using patients' own T lymphocytes. T cells play an important role in the immune system and can attack pathogens and cancer cells. T cell receptors (TCRs) can recognize different ligands with wide affinity and participate in activating various physiological processes. TCR cell therapy customizes functional TCR, which has the best antigen recognition characteristics and uses the human immune system to fight cancer. What is the molecular mechanism of this therapy?

    Recent advances in TCR signaling pathways

     

    TCR recognizes peptides that bind to MHC molecules (pMHC) presented by antigen presenting cells (APCs). The single TCR can recognize different ligands (auto-peptides and foreign-peptides) with wide affinity. TCR is involved in triggering different functional outputs. In thymus, the binding intensity of pMHC and TCR signals determines the process of cell development and differentiation. When the binding force is between the minimum and the maximum, it promotes the survival of thymocytes and transforms into the mature stage of CD4 + CD8 - or CD4 - CD8 +. If TCR and pMHC are too low or too high, cell apoptosis will occur. Peripherally, the low affinity binding of autologous pMHC to TCR provides the strong survival signal necessary to maintain the initial T cells, and also promotes the full activation of autologous pMHC in high affinity with foreign antigens.

    The intensity of TCR signal is crucial for the production of appropriate T cells. TCR signal transduction response guides the successful differentiation of CD4+T cells and plays a key role in specific T cell subsets, such as regulatory T cells. The intensity and duration of TCR cells are related to the differentiation of memory T cells, and are also the basic determinants of T cell impotence or depletion. The TCR signal is regulated by biochemical and molecular mechanisms, leading to signal amplification or attenuation. The mechanism of TCR regulation is complex and diverse, but it can be divided into three basic levels: the regulation of early signal transduction effector molecules (such as key kinases and phosphatases); the development stage of signal molecules (regulation of specific expression); and the dynamic regulation of TCR signal intensity.

    Effect of TCR signal

    Activation of the TCR signal not only induces T cell proliferation and production of cytokines, but also promotes T cell differentiation and function. Therefore, it is necessary to promote the phase change of cell function, including cell migration ability, and metabolic mode. In recent years, considerable progress has been made in this area.

    1. TCR signal and cell metabolism

    The immune activation of T lymphocytes is a process of energy demand. Therefore, how TCR signal affects T cell metabolism has been paid attention to and studied. In resting T cells and memory T cells, mitochondria-dependent catabolic metabolic patterns, including the glucose oxidation process of TCA (tricarboxylic acid cycle) and the beta-oxidation process of fatty acids, provide the necessary metabolic requirements for the exercise of basic cellular functions. However, when T cells are activated, their metabolic processes will undergo re-planning to produce more carbon and ATP to meet the needs of rapid cell growth and proliferation, such as the rapid reduction of fatty acid beta-oxidation process and the enhancement of other metabolic pathways, including glycolysis and glutamine metabolism. More and more evidence shows that silk / threonine kinase and its products can coordinate TCR to regulate the metabolism of T cells, thus meeting the metabolic needs of 2.T cells in the immune response.

    1. TCR signal and T cell proliferation and cytokine production

    TCR signaling pathways involved in cell proliferation and cytokine production are independent and regulated by the diversity of CD3 ITAM. The diversity of CD3 ITAM also corresponds to the intensity of TCR stimulation, that is, weak TCR stimulation can induce the production of cytokines, but cell proliferation must have a strong enough TCR stimulation.

    1. Cytoskeleton rearrangement and TCR signal transmission

    Cytoskeleton rearrangement plays a key role in TCR signal transduction. A large number of early studies have shown that the cytoskeleton is involved in the formation of SMAC during the activation of TCR in T cells. TCR signal activates cytoskeleton rearrangement on the one hand, and is regulated by cytoskeleton rearrangement on the other hand. Both of them accomplish the transmission of the TCR signal and the subsequent rearrangement of cytoskeleton mediated by TCR signal, which promotes the migration and invasion of T cells.

    With the development of modern biotechnology, such as large-scale histology, protein isolation and identification, and high resolution imaging, great progress has been made in the research of TCR signals. These include the discovery of new signal transduction and regulatory molecules, and the further elucidation of new regulatory mechanisms.