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Immunology May 2012B-cell activation is triggered by the binding of antigen to the B-cell receptor (BCR). The early molecular events triggered by BCR binding of ligand have been... (Review)
Review
B-cell activation is triggered by the binding of antigen to the B-cell receptor (BCR). The early molecular events triggered by BCR binding of ligand have been well-characterized both biochemically and using optical microscopy techniques to visualize B-cell activation as it happens. However, we understand much less about the BCR before activation. For this reason, this review will address recent advances in our view of the structure, organization and dynamics of the resting, unstimulated BCR. These parameters have important implications for our understanding of the initiation of B-cell activation and will be discussed in the context of current models for BCR activation. These models include the conformation-induced oligomerization model, in which binding of antigen to monomeric BCR induces a pulling or twisting force causing conformational unmasking of a clustering interface in the Cμ4 domain. Conversely, the dissociation activation model proposes that BCRs exist in auto-inhibitory oligomers on the resting B-cell surface and binding of antigen promotes the dissociation of the BCR oligomer exposing phosphorylation residues within Igα/Igβ. Finally, the collision coupling model suggests that BCR are segregated from activating co-receptors or kinases and activation is associated with changes in BCR mobility on the cell surface, which allows for the functional interaction of these elements.
Topics: B-Lymphocytes; Cell Polarity; Humans; Ligands; Lymphocyte Activation; Protein Transport; Receptors, Antigen, B-Cell
PubMed: 22269039
DOI: 10.1111/j.1365-2567.2012.03564.x -
Advanced Drug Delivery Reviews May 2017The once nascent field of immunoengineering has recently blossomed to include approaches to deliver and present biomolecules to program diverse populations of... (Review)
Review
The once nascent field of immunoengineering has recently blossomed to include approaches to deliver and present biomolecules to program diverse populations of lymphocytes to fight disease. Building upon improved understanding of the molecular and physical mechanics of lymphocyte activation, varied strategies for engineering surfaces to activate and deactivate T-Cells, B-Cells and natural killer cells are in preclinical and clinical development. Surfaces have been engineered at the molecular level in terms of the presence of specific biological factors, their arrangement on a surface, and their diffusivity to elicit specific lymphocyte fates. In addition, the physical and mechanical characteristics of the surface including shape, anisotropy, and rigidity of particles for lymphocyte activation have been fine-tuned. Utilizing these strategies, acellular systems have been engineered for the expansion of T-Cells and natural killer cells to clinically relevant levels for cancer therapies as well as engineered to program B-Cells to better combat infectious diseases.
Topics: Animals; Antigen Presentation; Antigens, Surface; B-Lymphocytes; Cell Engineering; Humans; Killer Cells, Natural; Lymphocyte Activation; Lymphocytes; T-Lymphocytes
PubMed: 28501510
DOI: 10.1016/j.addr.2017.05.005 -
International Journal of Sports Medicine Aug 2022Monocyte and lymphocyte subpopulations exhibit functions that vary between the anti- and pro-inflammatory spectrum, such as classic CD16- and non-classical... (Review)
Review
Monocyte and lymphocyte subpopulations exhibit functions that vary between the anti- and pro-inflammatory spectrum, such as classic CD16- and non-classical CD16+monocytes, as well as T helper 2 lymphocytes (Th2), the Th1/Th17 lymphocytes ratio, and T regulatory lymphocytes (Treg). Metabolic disease-associated inflammation is accompanied by an imbalance in monocyte and lymphocyte phenotypes and functionality, as well as a stronger proportion of inflammatory subpopulations. These changes appear to be important for the development and progression of diseases like diabetes and cardiovascular disease. On the other hand, the regular practice of physical exercise is an important tool to restore the functionality of monocytes and lymphocytes, and to balance the subtypes ratio. However, key variables regarding exercise prescription, such as the type of exercise, intensity, and volume differentially impact on the acute and chronic immune response in individuals diagnosed with meta-inflammation diseases. Here, we discuss the impact of different physical exercise protocols, acutely and chronically, on monocytes and lymphocytes of individuals with metabolic disease-associated inflammation. In this review, we focus on the best effects of different exercise protocols to dose the "exercise pill" in different inflammatory status.
Topics: Exercise; Humans; Inflammation; Monocytes; T-Lymphocytes, Helper-Inducer; T-Lymphocytes, Regulatory
PubMed: 34902867
DOI: 10.1055/a-1720-0369 -
Cancer Research Communications Sep 2022CD19-redirected chimeric antigen receptor (CAR) T cells have shown remarkable activity against B-cell cancers. While second-generation CARs induce complete remission in...
UNLABELLED
CD19-redirected chimeric antigen receptor (CAR) T cells have shown remarkable activity against B-cell cancers. While second-generation CARs induce complete remission in >80% of patients with acute lymphoblastic leukemia, similar monotherapy induces long-term remissions in only 26% of patients with chronic lymphocytic leukemia (CLL). This disparity is attributed to cell-intrinsic effector defects in autologous CLL-derived T cells. However, the mechanisms by which leukemic cells impact CAR T-cell potency are poorly understood. Herein we describe an assay that recapitulates endogenous CLL-mediated T-cell defects in healthy donor CAR T cells. Contact with CLL cells insufficiently activates, but does not irreversibly impair, CAR T-cell function. This state is rescuable by strong antigenic stimulation or IL2, and is not driven by immune suppression. Rather, this activation defect is attributable to low levels of costimulatory molecules on CLL cells, and exogenous costimulation enhanced CAR T-cell activation. We next assessed the stimulatory phenotype of CLL cells derived from different niches within the same patient. Lymph node (LN)-derived CLL cells had a strong costimulatory phenotype and promoted better CAR T-cell degranulation and cytokine production than matched peripheral blood CLL cells. Finally, CD40L-activated CLL cells acquired a costimulatory phenotype similar to the LN-derived tumor and stimulated improved CAR T-cell proliferation, cytokine production, and cytotoxicity. Together, these data identify insufficient activation as a driver of poor CAR T-cell responses in CLL. The costimulatory phenotype of CLL cells drives differential CAR T-cell responses, and can be augmented by improving costimulatory signaling.
SIGNIFICANCE
CLL cells insufficiently activate CAR T cells, driven by low levels of costimulatory molecules on the tumor. LN-derived CLL cells are more costimulatory and mediate enhanced CAR T-cell killing. This costimulatory phenotype can be modeled via CD40 L activation, and the activated tumor promotes stronger CAR T-cell responses.
Topics: Humans; T-Lymphocytes; Leukemia, Lymphocytic, Chronic, B-Cell; Receptors, Chimeric Antigen; B-Lymphocytes; CD40 Ligand
PubMed: 36922932
DOI: 10.1158/2767-9764.CRC-22-0200 -
Mediators of Inflammation 2014Glucose and glutamine are important energetic and biosynthetic nutrients for T and B lymphocytes. These cells consume both nutrients at high rates in a... (Review)
Review
Glucose and glutamine are important energetic and biosynthetic nutrients for T and B lymphocytes. These cells consume both nutrients at high rates in a function-dependent manner. In other words, the pathways that control lymphocyte function and survival directly control the glucose and glutamine metabolic pathways. Therefore, lymphocytes in different functional states reprogram their glucose and glutamine metabolism to balance their requirement for ATP and macromolecule production. The tight association between metabolism and function in these cells was suggested to introduce the possibility of several pathologies resulting from the inability of lymphocytes to meet their nutrient demands under a given condition. In fact, disruptions in lymphocyte metabolism and function have been observed in different inflammatory, metabolic, and autoimmune pathologies. Regular physical exercise and physical activity offer protection against several chronic pathologies, and this benefit has been associated with the anti-inflammatory and immunomodulatory effects of exercise/physical activity. Chronic exercise induces changes in lymphocyte functionality and substrate metabolism. In the present review, we discuss whether the beneficial effects of exercise on lymphocyte function in health and disease are associated with modulation of the glucose and glutamine metabolic pathways.
Topics: Animals; Exercise; Glucose; Glutamine; Humans; Lymphocytes; Physical Conditioning, Animal
PubMed: 24987195
DOI: 10.1155/2014/326803 -
Annals of Allergy, Asthma & Immunology... Feb 2021Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by a chronic type 2 inflammatory response in the paranasal sinuses. Group 2 innate lymphoid cells... (Review)
Review
OBJECTIVE
Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by a chronic type 2 inflammatory response in the paranasal sinuses. Group 2 innate lymphoid cells (ILC2s) are potent innate immune cells that contribute to type 2 inflammation by producing cytokines such as interleukin (IL)-4, IL-5, and IL-13. There is increasing evidence suggesting that ILC2s play an important role in the CRSwNP pathogenesis.
DATA SOURCES
We reviewed published literature obtained through PubMed inquiries.
STUDY SELECTIONS
Studies relevant to the presence, function, and activation of ILC2s in CRSwNP were included.
RESULTS
Nasal polyps (NPs) are one of the first tissues in which human ILC2s were discovered, and many groups have since reported that these cells are highly elevated in NPs. ILC2s in NPs are also highly activated and produce type 2 cytokines in vivo. Mediators known to activate ILC2s, including receptor activator of nuclear factor kappa-Β ligand, thymic stromal lymphopoietin, various lipid mediators (including prostaglandin D and cysteinyl leukotrienes), IL-4, and IL-13 have also been shown to be elevated in NPs compared with healthy sinonasal tissue. Other well-known ILC2 activators, IL-25 and IL-33, are sometimes elevated in NPs in some countries. Furthermore, activation of ILC2s by means of 4 distinct transcriptional pathways (nuclear factor kappa-light-chain-enhancer of activated B cells, nuclear factor of activated T cells, signal transducer and activator of transcription 5, and signal transducer and activator of transcription 6) is needed for the most robust generation of type 2 cytokines.
CONCLUSION
ILC2-mediated type 2 inflammation plays a crucial role in the pathogenesis of CRSwNP. Targeting the upstream mediators responsible for activating ILC2s and the downstream products that these cells release may play an important role in modifying the inflammatory response and improving clinical outcomes in CRSwNP.
Topics: Animals; Asthma, Aspirin-Induced; Chronic Disease; Humans; Immunity, Innate; Lymphocytes; Nasal Polyps; Rhinitis; Sinusitis
PubMed: 32781240
DOI: 10.1016/j.anai.2020.08.001 -
Current Opinion in Immunology Dec 2023The proper functioning of cytotoxic lymphocytes, such as natural killer and CD8+ T cells, is essential for effective cancer-immunity and immunotherapy responses. The... (Review)
Review
The proper functioning of cytotoxic lymphocytes, such as natural killer and CD8+ T cells, is essential for effective cancer-immunity and immunotherapy responses. The differentiation of these cells is controlled by several transcription factors (TFs), including members of the activator protein (AP)-1 family. The activity of AP-1 family members is regulated by various immune signaling pathways, which can be triggered by activating or inhibitory receptors as well as cytokines. The target genes controlled by AP-1 TFs are central to generate immunity to pathogens or malignancies. Here, we provide an overview of the current understanding of how AP-1 TFs regulate cytotoxic lymphocytes.
Topics: Humans; Transcription Factor AP-1; CD8-Positive T-Lymphocytes; Antineoplastic Agents; Neoplasms; Cytokines; T-Lymphocytes, Cytotoxic
PubMed: 37931499
DOI: 10.1016/j.coi.2023.102397 -
Seminars in Immunology Dec 2012Immunological function requires metabolic support to suit the needs of lymphocytes at a variety of distinct differentiation and activation states. It is now evident that... (Review)
Review
Immunological function requires metabolic support to suit the needs of lymphocytes at a variety of distinct differentiation and activation states. It is now evident that the signaling pathways that drive lymphocyte survival and activity can directly control cellular metabolism. This linkage provides a mechanism by which activation and specific signaling pathways provide a supply of appropriate and required nutrients to support cell functions in a pro-active supply rather than consumption-based metabolic model. In this way, the metabolism and fuel choices of lymphocytes are guided to specifically match the anticipated needs. If the fuel choice or metabolic pathways of lymphocytes are dysregulated, however, metabolic checkpoints can become activated to disrupt immunological function. These changes are now shown in several immunological diseases and may open new opportunities to selectively enhance or suppress specific immune functions through targeting of glucose, lipid, or amino acid metabolism.
Topics: Cell Differentiation; Glucose; Humans; Lymphocyte Activation; Lymphocytes; Signal Transduction
PubMed: 23290889
DOI: 10.1016/j.smim.2012.12.002 -
British Journal of Pharmacology Nov 2017Cytotoxic lymphocytes encompass natural killer lymphocytes (cells) and cytotoxic T cells that include CD8+ T cells, natural killer (NK) T cells, γ, δ (γδ)-T cells... (Review)
Review
UNLABELLED
Cytotoxic lymphocytes encompass natural killer lymphocytes (cells) and cytotoxic T cells that include CD8+ T cells, natural killer (NK) T cells, γ, δ (γδ)-T cells and human CD4 + CD28- T cells. These cells play critical roles in inflammatory diseases and in controlling cancers and infections. Cytotoxic lymphocytes can be activated via a number of mechanisms that may involve dendritic cells, macrophages, cytokines or surface proteins on stressed cells. Upon activation, they secrete pro-inflammatory cytokines as well as anti-inflammatory cytokines, chemokines and cytotoxins to promote inflammation and the development of atherosclerotic lesions including vulnerable lesions, which are strongly implicated in myocardial infarctions and strokes. Here, we review the mechanisms that activate and regulate cytotoxic lymphocyte activity, including activating and inhibitory receptors, cytokines, chemokine receptors-chemokine systems utilized to home to inflamed lesions and cytotoxins and cytokines through which they affect other cells within lesions. We also examine their roles in human and mouse models of atherosclerosis and the mechanisms by which they exert their pathogenic effects. Finally, we discuss strategies for therapeutically targeting these cells to prevent the development of atherosclerotic lesions and vulnerable plaques and the challenge of developing highly targeted therapies that only minimally affect the body's immune system, avoiding the complications, such as increased susceptibility to infections, which are currently associated with many immunotherapies for autoimmune diseases.
LINKED ARTICLES
This article is part of a themed section on Targeting Inflammation to Reduce Cardiovascular Disease Risk. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.22/issuetoc and http://onlinelibrary.wiley.com/doi/10.1111/bcp.v82.4/issuetoc.
Topics: Animals; Atherosclerosis; Humans; Killer Cells, Natural; T-Lymphocytes
PubMed: 28471481
DOI: 10.1111/bph.13845 -
Clinical and Experimental Immunology Jan 2017Immunosurveillance requires the migration of lymphocytes and their activation to induce proliferation and effector function. Effective immunity requires an optimal... (Review)
Review
Immunosurveillance requires the migration of lymphocytes and their activation to induce proliferation and effector function. Effective immunity requires an optimal supply of nutrients to lymphocytes. Cells contain nutrient sensing apparatus such as adenosine 5'-monophosphate-activated protein kinase (AMPK) that surveys intracellular ATP levels. Immunity declines during ageing and one possibility is that the energy balance may be altered in old lymphocytes. This paper summarizes recent data identifying a convergence of senescence and nutrient signalling pathways in lymphocytes that inhibit both T cell and natural killer (NK) cell function during ageing. Significantly, these pathways can be inhibited to enhance the activity of these cells.
Topics: AMP-Activated Protein Kinases; Adenosine Triphosphate; Animals; Cellular Senescence; Energy Metabolism; Humans; Immunologic Surveillance; Killer Cells, Natural; Lymphocyte Activation; Signal Transduction; T-Lymphocytes
PubMed: 27690328
DOI: 10.1111/cei.12876