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Current Biology : CB Aug 1995T-cell activation requires costimulation in addition to the antigen-specific signal. Recent results suggest that distinct costimulatory molecules can specifically... (Review)
Review
T-cell activation requires costimulation in addition to the antigen-specific signal. Recent results suggest that distinct costimulatory molecules can specifically activate different types of T-cell response.
Topics: Animals; Lymphocyte Activation; Signal Transduction; T-Lymphocytes
PubMed: 7583143
DOI: 10.1016/s0960-9822(95)00175-8 -
Frontiers in Immunology 2022In 1986, Mosmann and Coffman identified 2 functionally distinct subsets of activated CD4 T cells, Th1 and Th2 cells, being key in distinct T cell mediated responses.... (Review)
Review
In 1986, Mosmann and Coffman identified 2 functionally distinct subsets of activated CD4 T cells, Th1 and Th2 cells, being key in distinct T cell mediated responses. Over the past three decades, our understanding of CD4 T cell differentiation has expanded and the initial paradigm of a dichotomic CD4 T cell family has been revisited to accommodate a constantly growing number of functionally distinct CD4 T helper and regulatory subpopulations. Of note, CD4 T cells with cytotoxic functions have also been described, initially in viral infections, autoimmune disorders and more recently also in cancer settings. Here, we provide an historical overview on the discovery and characterization of cytotoxic CD4 T cells, followed by a description of their mechanisms of cytotoxicity. We emphasize the relevance of these cells in disease conditions, particularly in cancer, and we provide insights on how to exploit these cells in immunotherapy.
Topics: CD4-Positive T-Lymphocytes; Lymphocyte Activation; T-Lymphocyte Subsets; T-Lymphocytes, Cytotoxic; Th2 Cells
PubMed: 35572552
DOI: 10.3389/fimmu.2022.867189 -
Nature Communications Jul 2021Metabolic programming and mitochondrial dynamics along with T cell differentiation affect T cell fate and memory development; however, how to control metabolic...
Metabolic programming and mitochondrial dynamics along with T cell differentiation affect T cell fate and memory development; however, how to control metabolic reprogramming and mitochondrial dynamics in T cell memory development is unclear. Here, we provide evidence that the SUMO protease SENP1 promotes T cell memory development via Sirt3 deSUMOylation. SENP1-Sirt3 signalling augments the deacetylase activity of Sirt3, promoting both OXPHOS and mitochondrial fusion. Mechanistically, SENP1 activates Sirt3 deacetylase activity in T cell mitochondria, leading to reduction of the acetylation of mitochondrial metalloprotease YME1L1. Consequently, deacetylation of YME1L1 suppresses its activity on OPA1 cleavage to facilitate mitochondrial fusion, which results in T cell survival and promotes T cell memory development. We also show that the glycolytic intermediate fructose-1,6-bisphosphate (FBP) as a negative regulator suppresses AMPK-mediated activation of the SENP1-Sirt3 axis and reduces memory development. Moreover, glucose limitation reduces FBP production and activates AMPK during T cell memory development. These data show that glucose limitation activates AMPK and the subsequent SENP1-Sirt3 signalling for T cell memory development.
Topics: AMP-Activated Protein Kinases; ATPases Associated with Diverse Cellular Activities; Acetylation; Allografts; Animals; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Cell Survival; Colonic Neoplasms; Cysteine Endopeptidases; Fructosediphosphates; GTP Phosphohydrolases; Glucose; Immunologic Memory; Metabolomics; Metalloendopeptidases; Mice; Mice, Inbred C57BL; Microscopy, Electron, Transmission; Mitochondria; Mitochondrial Dynamics; Mitochondrial Proteins; Oxidative Phosphorylation; Sirtuin 3; Sumoylation; T-Lymphocytes
PubMed: 34272364
DOI: 10.1038/s41467-021-24619-2 -
ACS Applied Materials & Interfaces Apr 2021A variety of bioactive materials developed to expand T cells for adoptive transfer into cancer patients are currently evaluated in the clinic. In most cases, T cell...
A variety of bioactive materials developed to expand T cells for adoptive transfer into cancer patients are currently evaluated in the clinic. In most cases, T cell activating biomolecules are attached to rigid surfaces or matrices and form a static interface between materials and the signaling receptors on the T cells. We hypothesized that a T cell activating polymer brush interface might better mimic the cell surface of a natural antigen-presenting cell, facilitating receptor movement and concomitant advantageous mechanical forces to provide enhanced T cell activating capacities. Here, as a proof of concept, we synthesized semiflexible polyisocyanopeptide (PIC) polymer-based immunobrushes equipped with T cell activating agonistic anti-CD3 (αCD3) and αCD28 antibodies placed on magnetic microbeads. We demonstrated enhanced efficiency of expansion of activated primary human T cells even at very low numbers of stimulating antibodies compared to rigid beads. Importantly, the immunobrush architecture appeared crucial for this improved T cell activating capacity. Immunobrushes outperform current benchmarks by producing higher numbers of T cells exhibiting a combination of beneficial phenotypic characteristics, such as reduced exhaustion marker expression, high cytokine production, and robust expression of cytotoxic hallmarks. This study indicates that semiflexible immunobrushes have great potential in making T cell-based immunotherapies more effective.
Topics: Antigen-Presenting Cells; Biocompatible Materials; Cell Proliferation; Humans; Lymphocyte Activation; Molecular Mimicry; Peptides; Polyurethanes; Proof of Concept Study; T-Lymphocytes
PubMed: 33797875
DOI: 10.1021/acsami.0c21994 -
Seminars in Immunology Dec 2012The mechanistic target of rapamycin (mTOR), an evolutionally conserved serine and threonine kinase, plays a critical role in the promotion of cell growth and... (Review)
Review
The mechanistic target of rapamycin (mTOR), an evolutionally conserved serine and threonine kinase, plays a critical role in the promotion of cell growth and proliferation via integration of cellular and environmental cues. In adaptive immunity, the mTOR pathway orchestrates multiple physiological processes including the development and homeostasis of T cells under steady state, and their subsequent activation and differentiation upon antigen recognition. Associated with such fate decisions is the dynamic reprogramming of T cell metabolic pathways, as naïve, activated and memory cells are defined by distinct bioenergetic and biosynthetic activities. Emerging evidence indicates that mTOR signaling intersects with T cell metabolism at two major levels to constitute a critical control mechanism of T cell fate decisions. First, as a central environmental sensor, mTOR links immune signaling and the availability of nutrients, especially amino acids. Second, mTOR activates specific metabolic pathways in T cells such as aerobic glycolysis (also known as the "Warburg effect") in a process dependent upon the induction of transcription factors MYC and HIF1α. Understanding how mTOR interplays with T cell metabolism to dictate T cell fates and functions will provide fundamental insights into the mechanism of immune responses and the development of novel therapeutics against immune-mediated diseases. In this review, we summarize the current advances on mTOR signaling and T cell metabolism in the control of development, homeostasis, activation and differentiation of T cells.
Topics: Animals; Cell Differentiation; Humans; Immunologic Memory; Lymphocyte Activation; T-Lymphocytes; TOR Serine-Threonine Kinases; Thymus Gland
PubMed: 23375549
DOI: 10.1016/j.smim.2012.12.004 -
Trends in Immunology Nov 2023Following stimulation, the T cell receptor (TCR) and its coreceptors integrate multiple intracellular signals to initiate T cell proliferation, migration, gene... (Review)
Review
Following stimulation, the T cell receptor (TCR) and its coreceptors integrate multiple intracellular signals to initiate T cell proliferation, migration, gene expression, and metabolism. Among these signaling molecules are the small GTPases RAS and RAP1, which induce MAPK pathways and cellular adhesion to activate downstream effector functions. Although many studies have helped to elucidate the signaling intermediates that mediate T cell activation, the molecules and pathways that keep naive T cells in check are less understood. Several recent studies provide evidence that RASA2 and RASA3, which are GAP1-family GTPase-activating proteins (GAPs) that inactivate RAS and RAP1, respectively, are crucial molecules that limit T cell activation and adhesion. In this review we describe recent data on the roles of RASA2 and RASA3 as gatekeepers of T cell activation and migration.
Topics: Humans; GTPase-Activating Proteins; Signal Transduction; Cell Adhesion; T-Lymphocytes; ras GTPase-Activating Proteins
PubMed: 37858490
DOI: 10.1016/j.it.2023.09.002 -
Immunological Reviews Nov 2013Ca(2+) mobilization and cytoskeletal reorganization are key hallmarks of T-cell activation, and their interdependence has long been recognized. Recent advances in the... (Review)
Review
Ca(2+) mobilization and cytoskeletal reorganization are key hallmarks of T-cell activation, and their interdependence has long been recognized. Recent advances in the field have elucidated the molecular pathways that underlie these events and have revealed several points of intersection. Ca(2+) signaling can be divided into two phases: initial events leading to release of Ca(2+) from endoplasmic reticulum stores, and a second phase involving STIM 1 (stromal interaction molecule 1) clustering and CRAC (calcium release activated calcium) channel activation. Cytoskeletal dynamics promote both phases. During the first phase, the actin cytoskeleton promotes mechanotransduction and serves as a dynamic scaffold for microcluster assembly. Proteins that drive actin polymerization such as WASp (Wiskott-Aldrich syndrome protein) and HS1 (hematopoietic lineage cell-specific protein 1) promote signaling through PLCγ1 (phospholipase Cγ1) and release of Ca(2+) from endoplasmic reticulum stores. During the second phase, the WAVE (WASP-family verprolin homologous protein) complex and the microtubule cytoskeleton promote STIM 1 clustering at sites of plasma membrane apposition, opening Orai channels. In addition, gross cell shape changes and organelle movements buffer local Ca(2+) levels, leading to sustained Ca(2+) mobilization. Conversely, elevated intracellular Ca(2+) activates cytoskeletal remodeling. This can occur indirectly, via calpain activity, and directly, via Ca(2+) -dependent cytoskeletal regulatory proteins such as myosin II and L-plastin. While it is true that the cytoskeleton regulates Ca(2+) responses and vice versa, interdependence between Ca(2+) and the cytoskeleton also encompasses signaling events that occur in parallel, downstream of shared intermediates. Inositol cleavage by PLCγ1 simultaneously triggers both endoplasmic reticulum store release and diacylglycerol-dependent microtubule organizing center reorientation, while depleting the pool of phosphatidylinositol-4,5-bisphosphate, an activator of multiple actin-regulatory proteins. The close interdependence of Ca(2+) signaling and cytoskeletal dynamics in T cells provides positive feedback mechanisms for T-cell activation and allows for finely tuned responses to extracellular cues.
Topics: Actins; Animals; Calcium; Calcium Signaling; Cell Movement; Cytoskeletal Proteins; Cytoskeleton; Humans; Lymphocyte Activation; Organelles; Receptors, Antigen, T-Cell; T-Lymphocytes
PubMed: 24117814
DOI: 10.1111/imr.12123 -
BMC Genomics Mar 2021Bi-specific T-cell engager (BiTE) antibody is a class of bispecific antibodies designed for cancer immunotherapy. Blinatumomab is the first approved BiTE to treat acute...
BACKGROUND
Bi-specific T-cell engager (BiTE) antibody is a class of bispecific antibodies designed for cancer immunotherapy. Blinatumomab is the first approved BiTE to treat acute B cell lymphoblastic leukemia (B-ALL). It brings killer T and target B cells into close proximity, activating patient's autologous T cells to kill malignant B cells via mechanisms such as cytolytic immune synapse formation and inflammatory cytokine production. However, the activated T-cell subtypes and the target cell-dependent T cell responses induced by blinatumomab, as well as the mechanisms of resistance to blinatumomab therapy are largely unknown.
RESULTS
In this study, we performed single-cell sequencing analysis to identify transcriptional changes in T cells following blinatumomab-induced T cell activation using single cells from both, a human cell line model and a patient-derived model of blinatumomab-mediated cytotoxicity. In total, the transcriptome of 17,920 single T cells from the cell line model and 2271 single T cells from patient samples were analyzed. We found that CD8+ effector memory T cells, CD4+ central memory T cells, naïve T cells, and regulatory T cells were activated after blinatumomab treatment. Here, blinatumomab-induced transcriptional changes reflected the functional immune activity of the blinatumomab-activated T cells, including the upregulation of pathways such as the immune system, glycolysis, IFNA signaling, gap junctions, and IFNG signaling. Co-stimulatory (TNFRSF4 and TNFRSF18) and co-inhibitory (LAG3) receptors were similarly upregulated in blinatumomab-activated T cells, indicating ligand-dependent T cell functions. Particularly, B-ALL cell expression of TNFSF4, which encodes the ligand of T cell co-stimulatory receptor TNFRSF4, was found positively correlated with the response to blinatumomab treatment. Furthermore, recombinant human TNFSF4 protein enhanced the cytotoxic activity of blinatumomab against B-ALL cells.
CONCLUSION
These results reveal a target cell-dependent mechanism of T-cell activation by blinatumomab and suggest that TNFSF4 may be responsible for the resistant mechanism and a potential target for combination therapy with blinatumomab, to treat B-ALL or other B-cell malignancies.
Topics: Antibodies, Bispecific; Antineoplastic Agents; Humans; Lymphocyte Activation; OX40 Ligand; T-Lymphocytes; Transcriptome
PubMed: 33648458
DOI: 10.1186/s12864-021-07435-2 -
Immunological Reviews May 2020The complement system represents one of the evolutionary oldest arms of our immune system and is commonly recognized as a liver-derived and serum-active system critical... (Review)
Review
The complement system represents one of the evolutionary oldest arms of our immune system and is commonly recognized as a liver-derived and serum-active system critical for providing protection against invading pathogens. Recent unexpected findings, however, have defined novel and rather "uncommon" locations and activities of complement. Specifically, the discovery of an intracellularly active complement system-the complosome-and its key role in the regulation of cell metabolic pathways that underly normal human T cell responses have taught us that there is still much to be discovered about this system. Here, we summarize the current knowledge about the emerging functions of the complosome in T cell metabolism. We further place complosome activities among the non-canonical roles of other intracellular innate danger sensing systems and argue that a "location-centric" view of complement evolution could logically justify its close connection with the regulation of basic cell physiology.
Topics: Animals; Biomarkers; Complement Activation; Complement System Proteins; Disease Susceptibility; Energy Metabolism; Homeostasis; Humans; Lymphocyte Activation; T-Lymphocyte Subsets; T-Lymphocytes
PubMed: 32166778
DOI: 10.1111/imr.12852 -
Nature Biomedical Engineering Jan 2021The function of a T cell depends on its subtype and activation state. Here, we show that imaging of the autofluorescence lifetime signals of quiescent and activated T...
The function of a T cell depends on its subtype and activation state. Here, we show that imaging of the autofluorescence lifetime signals of quiescent and activated T cells can be used to classify the cells. T cells isolated from human peripheral blood and activated in culture using tetrameric antibodies against the surface ligands CD2, CD3 and CD28 showed specific activation-state-dependent patterns of autofluorescence lifetime. Logistic regression models and random forest models classified T cells according to activation state with 97-99% accuracy, and according to activation state (quiescent or activated) and subtype (CD3CD8 or CD3CD4) with 97% accuracy. Autofluorescence lifetime imaging can be used to non-destructively determine T-cell function.
Topics: Cells, Cultured; Humans; Lymphocyte Activation; Optical Imaging; T-Lymphocytes
PubMed: 32719514
DOI: 10.1038/s41551-020-0592-z