T Cells:Regulation and Cellular Immunity
Constantin A. Bona, Francisco A. Bonilla in Textbook of Immunology, 2019
Activating signals are generated in T cells by the interaction of several cell surface molecules with their respective ligands. These include the TCR-CD3 complex and all of the accessory molecules described above. One prominent second-messenger system is phosphoinositide (PI) metabolism which leads to mobilization of intracellular stores of calcium, and activation of protein kinase C (and a host of other kinases and regulatory proteins, Figure 6–12). Several of the surface molecules involved in signal transduction are themselves either kinases, phosphatases, or substrates for these enzymes (also see a discussion of very similar pathways in B cell activation in Chapter 5). Eventually, signals are carried into the nucleus where certain genes are activated. These include proto-oncogenes such as c-myc and c-fos, as well as genes critical for the initiation of T cell cycling such as IL-2 and the IL-2R α chain. The simultaneous production of the cytokine IL-2, and a component of its high-affinity receptor (IL-2R α), sets in motion a positive feedback loop that is important for T cell proliferation. Activation also induces the expression of additional surface molecules, the “activation antigens,” and the profile of cytokines which will determine the role the T cell plays in the immune response.
Therapies
Marc H. De Baets, Hans J.G.H. Oosterhuis in Myasthenia Gravis, 2019
The antigen-specific surface receptor of T cells binds to a peptide fragment of antigen that is bound to a histocompatibility (HLA) molecule expressed on the surface of an antigen-presenting cell, thus forming a trimolecular complex of antigen, T cell receptor, and histocompatibility (HLA) molecule.85-87 Recognition of antigen by the specific T cell receptor then leads to activation of the T cell via a cascade of signaling events common to all T cells. The basis for attempts to manipulate T cell activation at the level of the trimolecular complex are observations that the trimolecular complex is highly restricted in some EAE models.85-87 In such model situations, only few T cell receptor families participate in the recognition of certain “immunodominant” regions of antigen. Further, only certain types of the highly polymorphic histocompatibility molecules seem to bind the appropriate autoantigen determinants and present them to T cells. In EAE it is possible to selectively inhibit the autoreactive T cells with, for example, monoclonal antibodies against T cell receptor determinants or histocompatibility molecules. Other strategies employ peptides representing either T cell receptor determinants or nonpathogenic “relatives” of the autoantigen.85-87
Delivery of Immune Checkpoint Inhibitors Using Nanoparticles
Hala Gali-Muhtasib, Racha Chouaib in Nanoparticle Drug Delivery Systems for Cancer Treatment, 2020
A single signal is not enough for T cell activation; a T cell is not activated when the TCR (T cell receptor) binds an antigen-bound MHCI complex. T cell activation requires an additional signal viz. the binding of co-receptors. This second signal has been termed co-stimulation. In T cells, the second signal takes place when CD28 present on T cells binds to CD86 (B7-2) or CD80 (B7-1) expressed by APCs [16–18]. These co-receptors or co-stimulants, when active, act as accelerators that promote the T cell activation and, hence, the immune response. However, it was later discovered that some co-receptors act, in fact, as brakes that reduce the activation of T cells. These brake co-receptors are required, as mentioned above, to avoid an exaggerated and damaging immune response. The brakes inhibitory signaling pathways, are termed the immune checkpoints, and constitute any signal that inhibit priming of T cell activation or any signal that reduce an already initiated T cell response [19].
Regulatory T cells and CD20+ B cells in pediatric very severe aplastic anemia: possible clinical markers for evaluating the therapeutic efficacy and prognosis
Published in Hematology, 2018
Junyue Fang, Li Lin, Ying Wang, Dijin Lin, Chunyue Liu, Qiaozi Sunlong, Xianghua Lin
Severe aplastic anemia (SAA) is a refractory disease caused by an immune attack against hematopoietic stem and progenitor cells. This attack results in bone marrow failure characterized by signs of hypoplasia, pancytopenia and fatty bone marrow [1,2]. SAA in childhood remains life-threatening. Various mechanisms are concomitantly involved in this disorder. Moreover, SAA may have complicated pathological process, causing difficulties in treatment and poor prognosis. Particularly, patients with very severe aplastic anemia (VSAA) with extremely low neutrophils, platelets and overly low marrow hyperplasia have higher early death rate. Recent studies have shown that hematopoietic cells are destroyed by activated T cells in SAA [3–5]. However, the mechanism of T cell activation remains unclear. In 1995, Sakaguchi first defined Tregs as a special functional T cell subset [6]. It is vital in the maintenance of homeostasis and closely related to the occurrence of autoimmune diseases. Foxp3 is a specific marker in CD4+CD25+ Tregs and is essential for Tregs differentiation from naive CD4+ T cells [7]. Foxp3+ Treg is characterized by high expression of CD25 and low expression of CD127 [8]. With the progress in Tregs research, more and more scholars consider CD4+ CD25+ CD127dim T cells as Tregs.
The comprehensive molecular landscape of the immunologic co-stimulator B7 and TNFR ligand receptor families in colorectal cancer: immunotherapeutic implications with microsatellite instability
Published in OncoImmunology, 2018
Jinghua Tang, Wu Jiang, Dingxin Liu, Jun Luo, Xiaodan Wu, Zhizhong Pan, Peirong Ding, Yingqin Li
T cell plays an essential role in regulating immune responses and are activated by two classical signals: antigen recognition (signal one) and co-stimulation (signal two).16 The T cell co-stimulation molecules are key regulators of T-cell activation, tolerance, and exhaustion.17 Modification of these pathway alterations has been translated into effective strategies for cancer treatment. Presently, the co-stimulation pathways mainly involve two major families: the B7 family of immunoglobulins3 and the tumor necrosis factor receptor (TNFR) superfamily.18,19 The B7 family has 10 reported members, including CD80 (B7-1), CD86 (B7-2), PD-L1 (B7-H1), B7-H2, B7-H3, B7-DC, B7-H4, B7-H5, B7-H6 and B7-H7.18 These proteins have been proven to regulate both T cell co-stimulatory and co-inhibitory pathways.5,20 The TNFR superfamily proteins are expressed by antigen-presenting cells (APC) or tumor cells, functioning as important secondary signals: OX40L (TNFSF4), CD40 (TNFRSF5), CD70 (TNFSF7), CD137L (TNFSF9), HVEM (TNFRSF14), and GITRL (TNFSF18).19 Previous studies find that many of these molecules are dysregulated and associated with prognosis in different cancer types.21,22 Moreover, the well-known B7-1 or B7-2/CTLA-4 and PD-L1/PD-1 pathways are promising targets for tumor immune checkpoint therapy.5,23 However, the systemic alteration of these families has not been defined in CRC.
The role of immune checkpoint inhibitors in advanced non-small cell lung cancer
Published in Expert Review of Respiratory Medicine, 2019
Nikolaos F Pistamaltzian, Vassilis Georgoulias, Athanasios Kotsakis
Increasing evidence from current research suggests that adaptive immunity plays a major role in regulating the growth of tumor cells. T-cells have a central role in coordinating the immune response against tumor-specific neo-antigens, during oncogenesis. T-cell activation consists of two major steps. In the first step, T-cell receptor (TCR) recognizes the antigen and in the second step, co-stimulation in the form of TCR interactions between T-cell and dendritic cells (DCs) takes place. While T-cell activation depends on the initial tumor antigen-specific signal provided to the TCRs via the antigen-loaded major histocompatibility complex (MHC) on DCs, additional signals provided by costimulatory molecules fine-tune this response, determining its strength, nature, and duration. The relatively recent discovery of receptors regulating T cell activation, also called immune-checkpoints, against the autologous tumor cells was of paramount importance for understanding how cancer progresses under immunosurveillance [9–12].
Related Knowledge Centers
- Adaptive Immune System
- Thymus
- White Blood Cell
- Hematopoietic Stem Cell
- Bone Marrow
- Immune System
- Lymphocyte
- Cell Surface Receptor
- T-Cell Receptor
- Immune Response