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Biochemical Society Transactions Dec 2014Protein kinase Cθ (PKCθ) is a key enzyme in T-lymphocytes where it plays an important role in signal transduction downstream of the activated T-cell receptor (TCR) and... (Review)
Review
Protein kinase Cθ (PKCθ) is a key enzyme in T-lymphocytes where it plays an important role in signal transduction downstream of the activated T-cell receptor (TCR) and the CD28 co-stimulatory receptor. Antigenic stimulation of T-cells triggers PKCθ translocation to the centre of the immunological synapse (IS) at the contact site between antigen-specific T-cells and antigen-presenting cells (APCs). The IS-residing PKCθ phosphorylates and activates effector molecules that transduce signals into distinct subcellular compartments and activate the transcription factors, nuclear factor κB (NF-κB), nuclear factor of activated T-cells (NFAT) and activating protein 1 (AP-1), which are essential for the induction of T-cell-mediated responses. Besides its major biological role in T-cells, PKCθ is expressed in several additional cell types and is involved in a variety of distinct physiological and pathological phenomena. For example, PKCθ is expressed at high levels in platelets where it regulates signal transduction from distinct surface receptors, and is required for optimal platelet activation and aggregation, as well as haemostasis. In addition, PKCθ is involved in physiological processes regulating insulin resistance and susceptibility to obesity, and is expressed at high levels in gastrointestinal stromal tumours (GISTs), although the functional importance of PKCθ in these processes and cell types is not fully clear. The present article briefly reviews selected topics relevant to the biological roles of PKCθ in health and disease.
Topics: Disease; Humans; Isoenzymes; Lymphocyte Activation; Platelet Activation; Platelet Aggregation; Protein Kinase C; Protein Kinase C-theta; Signal Transduction; T-Lymphocytes
PubMed: 25399558
DOI: 10.1042/BST20140180 -
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 -
ELife Apr 2023The activation of Sphingosine-1-phosphate receptor 1 (S1PR1) by S1P promotes lymphocyte egress from lymphoid organs, a process critical for immune surveillance and T...
The activation of Sphingosine-1-phosphate receptor 1 (S1PR1) by S1P promotes lymphocyte egress from lymphoid organs, a process critical for immune surveillance and T cell effector activity. Multiple drugs that inhibit S1PR1 function are in use clinically for the treatment of autoimmune diseases. Cluster of Differentiation 69 (CD69) is an endogenous negative regulator of lymphocyte egress that interacts with S1PR1 in cis to facilitate internalization and degradation of the receptor. The mechanism by which CD69 causes S1PR1 internalization has been unclear. Moreover, although there are numerous class A GPCR structures determined with different small molecule agonists bound, it remains unknown whether a transmembrane protein per se can act as a class A GPCR agonist. Here, we present the cryo-EM structure of CD69-bound S1PR1 coupled to the heterotrimeric G complex. The transmembrane helix (TM) of one protomer of CD69 homodimer contacts the S1PR1-TM4. This interaction allosterically induces the movement of S1PR1-TMs 5-6, directly activating the receptor to engage the heterotrimeric G. Mutations in key residues at the interface affect the interactions between CD69 and S1PR1, as well as reduce the receptor internalization. Thus, our structural findings along with functional analyses demonstrate that CD69 acts in cis as a protein agonist of S1PR1, thereby promoting G-dependent S1PR1 internalization, loss of S1P gradient sensing, and inhibition of lymphocyte egress.
Topics: Immunologic Factors; Lymphocytes; Membrane Proteins; Receptors, Lysosphingolipid; T-Lymphocytes
PubMed: 37039481
DOI: 10.7554/eLife.88204 -
Dermatologie (Heidelberg, Germany) Dec 2022Melanoma is a highly immunogenic cancer with an increased infiltration of lymphocytes (TIL). TIL are a very heterogeneous population which consists among others of... (Review)
Review
Melanoma is a highly immunogenic cancer with an increased infiltration of lymphocytes (TIL). TIL are a very heterogeneous population which consists among others of CD8+ T cells, CD4+ T cells, regulatory T cells, B cells, and natural killer (NK) cells and may differ highly between melanoma patients. Distribution, concentration, phenotype, and activation status of the infiltrating lymphocytes vary greatly and impact the prognosis. Different subpopulations of CD8+ T cells, CD4+ T cells, and NK cells have been identified and have been associated with both the course of the disease and the therapeutic response to different therapies. Increased knowledge of the different functions, interactions, activation, and possibilities of actively influencing relevant subgroups may lead to novel, innovative, and promising therapeutic options.
Topics: Humans; Melanoma; Lymphocyte Count; Killer Cells, Natural; CD8-Positive T-Lymphocytes; CD4-Positive T-Lymphocytes
PubMed: 36401123
DOI: 10.1007/s00105-022-05076-4 -
Nature Reviews. Immunology Oct 2014The cellular progeny of a clonally selected lymphocyte must execute function. However, their function must often occur in more than one way, in more than one place and... (Review)
Review
The cellular progeny of a clonally selected lymphocyte must execute function. However, their function must often occur in more than one way, in more than one place and at more than one time. Experimental evidence supports the view that a single activated lymphocyte can produce a variety of cellular descendants. The mechanisms that are responsible for generating diversity among the progeny of a single lymphocyte remain a subject of lively controversy. Some groups have suggested stochastic mechanisms that are analogous to the diversification of the antigen receptor repertoire. We suggest that the complexity of lymphocyte fates in space and time can be derived from a single naive lymphocyte using the principles of cell diversification that are common in developmental and regenerative biology, including (but not limited to) asymmetric cell division.
Topics: Animals; B-Lymphocytes; Cell Differentiation; Cell Division; Dendritic Cells; Humans; Lymphocyte Activation; Lymphocytes; Models, Immunological; Receptors, Antigen, B-Cell; Receptors, Antigen, T-Cell; T-Lymphocytes
PubMed: 25190286
DOI: 10.1038/nri3734 -
Oncoimmunology Feb 2021The tumor microenvironment includes a complex network of cytokines and chemokines that contribute to shaping the intratumoral immune reaction. Understanding the... (Review)
Review
The tumor microenvironment includes a complex network of cytokines and chemokines that contribute to shaping the intratumoral immune reaction. Understanding the mechanisms leading to immune-hot (Immunoscore-high) altered (excluded and immunosuppressed) and cold tumors are of critical importance for successful anti-cancer therapies. Two essential mechanisms are highlighted. Specific chemokines and adhesion molecules appeared to target and attract immune effector T cells to the tumor microenvironment and to specific regions within the tumor. These mechanisms are dependent upon intratumoral IL-15 expression. Decreased IL15 expression also affected the local proliferation of B and T lymphocytes. A comprehensive analysis revealed a major contribution of IL15 in shaping the tumor immune contexture. Thus, an lymphocytic infiltration is mediated through chemokines and attraction inside or around the tumor microenvironment, and an IL15-mediated lymphocytic proliferation, which expand the local pool of intratumoral cytotoxic CD8 T-cells are key determinants of the immune contexture. Increased IL15 expression and local proliferation of T-cells were associated with decreased risk of tumor recurrence and prolonged survival of cancer patients. These data provide further mechanisms to prioritize research and help in designing better therapeutic interventions.
Topics: CD8-Positive T-Lymphocytes; Cell Proliferation; Humans; Interleukin-15; Lymphocyte Activation; T-Lymphocytes, Cytotoxic
PubMed: 33628626
DOI: 10.1080/2162402X.2021.1886726 -
Mucosal Immunology Sep 2020Intraepithelial T lymphocytes (T-IEL) contain subsets of innate-like T cells that evoke innate and adaptive immune responses to provide rapid protection at epithelial... (Review)
Review
Intraepithelial T lymphocytes (T-IEL) contain subsets of innate-like T cells that evoke innate and adaptive immune responses to provide rapid protection at epithelial barrier sites. In the intestine, T-IEL express variable T cell antigen receptors (TCR), with unknown antigen specificities. Intriguingly, they also express multiple inhibitory receptors, many of which are normally found on exhausted or antigen-experienced T cells. This pattern suggests that T-IEL are antigen-experienced, yet it is not clear where, and in what context, T-IEL encounter TCR ligands. We review recent evidence indicating TCR antigens for intestinal innate-like T-IEL are found on thymic or intestinal epithelium, driving agonist selection of T-IEL. We explore the contributions of the TCR and various co-stimulatory and co-inhibitory receptors in activating T-IEL effector functions. The balance between inhibitory and activating signals may be key to keeping these highly cytotoxic, rapidly activated cells in check, and key to harnessing their immune surveillance potential.
Topics: Animals; Antigens; Biomarkers; Costimulatory and Inhibitory T-Cell Receptors; Epitopes, T-Lymphocyte; Humans; Immunity, Innate; Intraepithelial Lymphocytes; Lymphocyte Activation; NK Cell Lectin-Like Receptor Subfamily K; Receptors, Antigen, T-Cell; T-Lymphocyte Subsets
PubMed: 32415229
DOI: 10.1038/s41385-020-0294-6 -
Exercise and Sport Sciences Reviews Jul 2017Hematopoietic stem cell (HSC) transplantation and adoptive transfer immunotherapy are effective in treating blood cancers and posttransplant infections, but... (Review)
Review
Hematopoietic stem cell (HSC) transplantation and adoptive transfer immunotherapy are effective in treating blood cancers and posttransplant infections, but low-circulating cell numbers in patients and donors are oftentimes a limiting factor. We postulate that a single exercise bout will increase the yield of patient- and donor-derived HSCs and cytotoxic lymphocytes to improve this form of treatment for cancer patients.
Topics: Exercise; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Humans; Immunotherapy, Adoptive; Killer Cells, Natural; Lymphocyte Count; Neoplasms; T-Lymphocytes
PubMed: 28418996
DOI: 10.1249/JES.0000000000000114 -
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 -
Methods in Molecular Biology (Clifton,... 2023B cells engaging with antigen and secondary signals provided by T cell help, or ligands for Toll-like receptors, undergo a step-wise process of differentiation to...
B cells engaging with antigen and secondary signals provided by T cell help, or ligands for Toll-like receptors, undergo a step-wise process of differentiation to eventually produce antibody-secreting plasma cells. During the course of this conversion, the cells transition from a resting, non-growing state to an activated B-cell state engaged in DNA synthesis and mitosis to a terminally differentiated, quiescent cell state with expanded organelles necessary for high levels of secretion. Each of these phases is accompanied by considerable changes in metabolic requirements. To facilitate evaluation of this metabolic reprogramming, methods for the in vitro differentiation of human B cells that incorporates each of the transitional stages are described.
Topics: Humans; B-Lymphocytes; Lymphocyte Activation; T-Lymphocytes; Antibody-Producing Cells; Cell Differentiation; Plasma Cells
PubMed: 37258770
DOI: 10.1007/978-1-0716-3247-5_20