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Current Opinion in Virology Feb 2016Pathogens such as the human immunodeficiency virus (HIV), the hepatitis B and C virus (HBV, HCV) and certain strains of the rodent lymphocytic choriomeningitis virus... (Review)
Review
Pathogens such as the human immunodeficiency virus (HIV), the hepatitis B and C virus (HBV, HCV) and certain strains of the rodent lymphocytic choriomeningitis virus (LCMV) establish a state of persisting viral replication. This occurs besides strong adoptive immune responses and the induction of large numbers of activated pathogen-specific T-cells. The failure of the immune system to clear these viruses is typically attributed to a loss of effector T-cell function-a phenomenon referred to as T-cell exhaustion. Though largely accepted, this loss of function concept is being more and more challenged by comprehensive clinical and experimental observations which highlight that T-cells in chronic infections are more functional than previously considered. Here, we highlight examples that demonstrate that such T-cells mediate a profound form of immune-surveillance. We also briefly discuss the opportunities and limitations of employing 'exhausted' T-cells for therapeutic purposes.
Topics: Animals; Cell Differentiation; Chronic Disease; Host-Pathogen Interactions; Humans; Immunity, Heterologous; Immunologic Memory; Immunologic Surveillance; Immunomodulation; Lymphocyte Activation; T-Lymphocytes; Virus Diseases
PubMed: 26826950
DOI: 10.1016/j.coviro.2016.01.002 -
Journal of Clinical Immunology Aug 2023A subset of common variable immunodeficiency (CVID) patients either presents with or develops autoimmune and lymphoproliferative complications, such as granulomatous...
PURPOSE
A subset of common variable immunodeficiency (CVID) patients either presents with or develops autoimmune and lymphoproliferative complications, such as granulomatous lymphocytic interstitial lung disease (GLILD), a major cause of morbidity and mortality in CVID. While a myriad of phenotypic lymphocyte derangements has been associated with and described in GLILD, defects in T and B cell antigen receptor (TCR/BCR) signaling in CVID and CVID with GLILD (CVID/GLILD) remain undefined, hindering discovery of biomarkers for disease monitoring, prognostic prediction, and personalized medicine approaches.
METHODS
To identify perturbations of immune cell subsets and TCR/BCR signal transduction, we applied mass cytometry analysis to peripheral blood mononuclear cells (PBMCs) from healthy control participants (HC), CVID, and CVID/GLILD patients.
RESULTS
Patients with CVID, regardless of GLILD status, had increased frequency of HLADRCD4 T cells, CD57CD8 T cells, and CD21 B cells when compared to healthy controls. Within these cellular populations in CVID/GLILD patients only, engagement of T or B cell antigen receptors resulted in discordant downstream signaling responses compared to CVID. In CVID/GLILD patients, CD21 B cells showed perturbed BCR-mediated phospholipase C gamma and extracellular signal-regulated kinase activation, while HLADRCD4 T cells and CD57CD8 T cells displayed disrupted TCR-mediated activation of kinases most proximal to the receptor.
CONCLUSION
Both CVID and CVID/GLILD patients demonstrate an activated T and B cell phenotype compared to HC. However, only CVID/GLILD patients exhibit altered TCR/BCR signaling in the activated lymphocyte subsets. These findings contribute to our understanding of the mechanisms of immune dysregulation in CVID with GLILD.
Topics: Humans; Lung Diseases, Interstitial; Common Variable Immunodeficiency; CD8-Positive T-Lymphocytes; Leukocytes, Mononuclear; Lymphocytes; Signal Transduction; Receptors, Antigen, B-Cell; Receptors, Antigen, T-Cell
PubMed: 37093407
DOI: 10.1007/s10875-023-01485-9 -
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 Immunopathology Jan 2017The development of T helper cell subsets requires activated T cells that respond to a polarizing cytokine environment resulting in the activation and expression of... (Review)
Review
The development of T helper cell subsets requires activated T cells that respond to a polarizing cytokine environment resulting in the activation and expression of transcription factors. The subset-specific transcription factors bind and induce the production of specific effector cytokines. Th9 cells express IL-9 and develop in the presence of TGFβ, IL-4, and IL-2. Each of these cytokines activates signaling pathways that are required for Th9 differentiation and IL-9 production. In this review, I summarize what is currently understood about the signaling pathways and transcription factors that promote the Th9 genetic program, providing some perspective for the integration of the signals in regulating the Il9 gene and dictating the expression of other Th9-associated genes. I highlight how experiments in mouse cells have established a transcriptional network that is conserved in human T cells and set the stage toward defining the next important questions for a more detailed understanding of Th9 cell development and function.
Topics: Animals; Cell Differentiation; Cytokines; Gene Expression Regulation; Humans; Interleukin-9; Phenotype; Protein Binding; Protein Interaction Maps; Receptors, Antigen, T-Cell; Regulatory Sequences, Nucleic Acid; Signal Transduction; T-Lymphocyte Subsets; T-Lymphocytes, Helper-Inducer; Transcription Factors; Transcription, Genetic
PubMed: 27837254
DOI: 10.1007/s00281-016-0600-2 -
Trends in Immunology Jun 2017Immunological memory has long been described as a property of the adaptive immune system that results in potent responses on exposure to an antigen encountered... (Review)
Review
Immunological memory has long been described as a property of the adaptive immune system that results in potent responses on exposure to an antigen encountered previously. While this definition appears to exclude cells that do not express antigen receptors, recent studies have shown that innate immune cells, including natural killer (NK) cells, macrophages, and, more recently, group 2 innate lymphoid cells (ILC2s) can record previous activations and respond more vigorously on reactivation. Here we review the similarities and differences between these forms of memory and the underlying mechanisms. Based on these insights, we propose to revise the definition of immunological memory, as the capacity to remember being previously activated and respond more efficiently on reactivation regardless of antigen specificity.
Topics: Animals; Cell Differentiation; Cytokines; Humans; Immunity, Innate; Immunologic Memory; Killer Cells, Natural; Lymphocyte Activation; Lymphocytes; Macrophages; Th2 Cells; Transcriptome
PubMed: 28416448
DOI: 10.1016/j.it.2017.03.005 -
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 -
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 -
Journal of Molecular Medicine (Berlin,... Feb 2015It is becoming more and more accepted that, in addition to producing autoantibodies, B lymphocytes have other important functions that influence the development of... (Review)
Review
It is becoming more and more accepted that, in addition to producing autoantibodies, B lymphocytes have other important functions that influence the development of autoimmunity. For example, autoreactive B cells are able to produce inflammatory cytokines and activate pathogenic T cells. B lymphocytes can react to extracellular signals with a range of responses from anergy to autoreactivity. The final outcome is determined by the relative contribution of signaling events mediated by activating and inhibitory pathways. Besides the B cell antigen receptor (BCR), several costimulatory receptors expressed on B cells can also induce B cell proliferation and survival, or regulate antibody production. These include CD19, CD40, the B cell activating factor receptor, and Toll-like receptors. Hyperactivity of these receptors clearly contributes to breaking B-cell tolerance in several autoimmune diseases. Inhibitors of these activating signals (including protein tyrosine phosphatases, deubiquitinating enzymes and several adaptor proteins) are crucial to control B-cell activation and maintain B-cell tolerance. In this review, we summarize the inhibitory signaling mechanisms that counteract B-cell activation triggered by the BCR and the coreceptors.
Topics: Animals; Autoimmune Diseases; B-Lymphocytes; Humans; Immune Tolerance; Immunomodulation; Lymphocyte Activation; Molecular Targeted Therapy; Receptors, Antigen, B-Cell; Receptors, Immunologic; Signal Transduction
PubMed: 25627575
DOI: 10.1007/s00109-015-1252-8 -
European Journal of Cell Biology 2022tT cells migrate to lymphoid organs to become activated through specific contacts with antigen-presenting cells bearing foreign antigens. During migration and... (Review)
Review
tT cells migrate to lymphoid organs to become activated through specific contacts with antigen-presenting cells bearing foreign antigens. During migration and activation, T lymphocytes are exposed not only to diverse biochemical inputs, but also to different mechanical conditions. Passage from the blood or lymph to solid tissues involves lymphocyte rolling, firm arrest and diapedesis through endothelial monolayers. Throughout this process, cells are subjected to diverse fluid flow regimes. After extravasation, T lymphocytes crawl through viscoelastic media of different biochemical and mechanical properties and geometries. In lymph nodes, T cell contact with antigen-presenting cells is guided by rigidity cues and ligand-receptor interactions. T lymphocyte adaptation to diverse mechanical regimes involves multiple signaling and morphological modifications, many of which enable the conversion of mechanical forces into biochemical signals and vice-versa. These components enable T lymphocyte survival, homing and activation. Here, we review the mechanisms that enable T lymphocytes to survive and thrive under the different mechanical conditions they encounter during their life cycle. These processes require the integration of diverse signaling networks that convert extracellular mechano-chemical cues into force, movement and activation.
Topics: Cell Movement; Lymphocytes; Signal Transduction; T-Lymphocytes
PubMed: 35588542
DOI: 10.1016/j.ejcb.2022.151236 -
Frontiers in Immunology 2023Multiple sclerosis (MS) is a prevalent neuroimmunological illness that leads to neurological disability in young adults. Although the etiology of MS is heterogeneous, it... (Review)
Review
Multiple sclerosis (MS) is a prevalent neuroimmunological illness that leads to neurological disability in young adults. Although the etiology of MS is heterogeneous, it is well established that aberrant activity of adaptive and innate immune cells plays a crucial role in its pathogenesis. Several immune cell abnormalities have been described in MS and its animal models, including T lymphocytes, B lymphocytes, dendritic cells, neutrophils, microglia/macrophages, and astrocytes, among others. Physical exercise offers a valuable alternative or adjunctive disease-modifying therapy for MS. A growing body of evidence indicates that exercise may reduce the autoimmune responses triggered by immune cells in MS. This is partially accomplished by restricting the infiltration of peripheral immune cells into the central nervous system (CNS) parenchyma, curbing hyperactivation of immune cells, and facilitating a transition in the balance of immune cells from a pro-inflammatory to an anti-inflammatory state. This review provides a succinct overview of the correlation between physical exercise, immune cells, and MS pathology, and highlights the potential benefits of exercise as a strategy for the prevention and treatment of MS.
Topics: Animals; Multiple Sclerosis; Central Nervous System; T-Lymphocytes; Macrophages; Exercise
PubMed: 37841264
DOI: 10.3389/fimmu.2023.1260663