Aspects Of Immune Cell Function Research Articles

Determination of T-cell clonality and expression profiles of Toll-like receptors signaling pathway genes and related miRNAs in patients with mycosis fungoides

Cutaneous T-cell lymphomas (CTCL) encompass a group of diseases characterized by the presence of malignant clonal CD4+ T lymphocytes in the skin. Mycosis fungoides (MF) is the most prevalent form of CTCL, accounting for approximately 60 % of cutaneous T-cell lymphomas and 50 % of all primary cutaneous lymphomas. Despite ongoing research, the precise pathogenesis of MF remains incompletely understood. Toll-like receptors (TLRs) have the ability to specifically recognize ligands, subsequently induce the expression of diverse genes and activate innate immunity within the cell. Furthermore, miRNAs play a crucial role in regulating various aspects of immune cell function. The aim of our study was to explore the potential roles of TLRs and the genes implicated in their signal transduction, along with the expression status of miRNAs in the mechanisms underlying MF. Additionally, we assessed the clonal status and compared it with clinicopathological data using a T-cell clonality assay. To determine the expression status of TLR pathway genes and miRNAs, we conducted RT-PCR analysis on 52 MF samples and 50 control paraffin block materials. Pathway analysis were conducted using the KEGG database. T-cell receptor (TCR) gamma clonality changes were evaluated. Results from the study revealed increased expressions of TLR-1, -4, -8, IRF7, TRAF3, MEK1, MEK2, Elk1, NFkB, hsa-miR-21-5p, and hsa-miR-155-5p, as well as decreased expressions of hsa-miR-130a-3p, hsa-miR-210-3p, and hsa-let-7e-5p in the MF group. TCR gamma clonal change analysis demonstrated that 55.5 % of the analysed DNAs exhibited monoclonal and biallelic patterns, while 45.5 % displayed polyclonality. These findings collectively suggest the potential influence and therapeutic possibilities of the TLR signalling pathway in the molecular pathogenesis of MF.

The effect of resistance exercise on the immune cell function in humans: A systematic review.

Resistance exercise is beneficial for the immune system, including decreased susceptibility to infections and improved effectiveness of vaccinations. This review aims to provide a systematic analysis of the literature regarding the impact of resistance exercise on immune cells in the blood circulation. The protocol of this review followed the PRISMA guidelines and registered in PROSPERO (ID: CRD42020157834). PubMed and Web-of-Science were systematically searched for relevant articles. Outcomes were divided into two categories: 1) inflammatory gene expression or secretion of inflammation-related cytokines and 2) other aspects such as cell migration, proliferation, apoptosis, phagocytosis, and redox status. Thirty intervention studies were included in this review, of which 11 articles were randomized controlled trials and six non-randomized controlled trials. Although only resistance exercise interventions were included, there was a high heterogeneity regarding specific exercise modalities. The most frequently studied outcome measures were the gene and protein expression levels in peripheral blood mononuclear cells (PBMC). This review reveals that already one acute exercise bout activates the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway in PBMC. Although resistance exercise induces an acute cytosolic oxidative stress response, the antioxidant enzyme expression is improved after resistance training period. Natural killer cell activity increases in older but decreases in younger adults immediately after a resistance exercise bout. Moreover, resistance exercise improves neutrophil phagocytic activity. Finally, effects on lymphocyte proliferation remain unclear. The results of this systematic review demonstrate that resistance exercise has beneficial effects on several aspects of immune cell function both in young and older individuals. Acute changes in immune cell function occur already after a single bout of resistance exercise. However, regular resistance training during several weeks seems necessary to obtain beneficial adaptations that can be related to better immunity and reduced inflammation. The effects documented in this review confirm the beneficial effects of resistance exercise in young as well as older persons on the immune cell function.

Acidic Ca2+ stores and immune-cell function

Acidic organelles act as intracellular Ca2+ stores; they actively sequester Ca2+ in their lumina and release it to the cytosol upon activation of endo-lysosomal Ca2+ channels. Recent data suggest important roles of endo-lysosomal Ca2+ channels, the Two-Pore Channels (TPCs) and the TRPML channels (mucolipins), in different aspects of immune-cell function, particularly impacting membrane trafficking, vesicle fusion/fission and secretion. Remarkably, different channels on the same acidic vesicles can couple to different downstream physiology. Endo-lysosomal Ca2+ stores can act under different modalities, be they acting alone (via local Ca2+ nanodomains around TPCs/TRPMLs) or in conjunction with the ER Ca2+ store (to either promote or suppress global ER Ca2+ release). These different modalities impinge upon functions as broad as phagocytosis, cell-killing, anaphylaxis, immune memory, thrombostasis, and chemotaxis.

C5aR2 Activation Broadly Modulates the Signaling and Function of Primary Human Macrophages.

The complement activation fragment C5a is a potent proinflammatory mediator that is increasingly recognized as an immune modulator. C5a acts through two C5a receptors, C5aR1 (C5aR, CD88) and C5aR2 (C5L2, GPR77), to powerfully modify multiple aspects of immune cell function. Although C5aR1 is generally acknowledged to be proinflammatory and immune-activating, the potential roles played by C5aR2 remain poorly defined. Despite studies demonstrating C5aR2 can modulate C5aR1 in human cells, it is not yet known whether C5aR2 functionality is limited to, or requires, C5aR1 activation or influences immune cells more broadly. The present study, therefore, aimed to characterize the roles of C5aR2 on the signaling and function of primary human monocyte-derived macrophages, using a C5aR2 agonist (Ac-RHYPYWR-OH; P32) to selectively activate the receptor. We found that although C5aR2 activation with P32 by itself was devoid of any detectable MAPK signaling activities, C5aR2 agonism significantly dampened C5aR1-, C3aR-, and chemokine-like receptor 1 (CMKLR1)-mediated ERK signaling and altered intracellular calcium mobilization mediated by these receptors. Functionally, selective C5aR2 activation also downregulated cytokine production triggered by various TLRs (TLR2, TLR3, TLR4, and TLR7), C-type lectin receptors (Dectin-1, Dectin-2, and Mincle), and the cytosolic DNA sensor stimulator of IFN genes (STING). Surprisingly, activity at the C-type lectin receptors was particularly powerful, with C5aR2 activation reducing Mincle-mediated IL-6 and TNF-α generation by 80-90%. In sum, this study demonstrates that C5aR2 possesses pleiotropic functions in primary human macrophages, highlighting the role of C5aR2 as a powerful regulator of innate immune function.

TRPML Cation Channels in Inflammation and Immunity.

Background: In 1883, Ilya Mechnikov discovered phagocytes and established the concept of phagocytosis by macrophages. In 1908, he was awarded the Nobel Prize in Physiology/Medicine for his findings, which laid the foundations for today's understanding of the innate immune response. Only in the 1960s, Max Cooper and Robert Good significantly advanced our understanding of the immune system by demonstrating that B- and T-cells cooperate to regulate the adaptive immune response. Both, innate and adaptive immune response are essential to effectively protect the individual against infectious agents, such as viruses, bacterial or insect toxins, or allergens. Innate immune responses occur rapidly upon exposure to noxious or infectious agents or organisms, in contrast to the adaptive immune system that needs days rather than hours to develop and acts primarily on the basis of antigen-specific receptors expressed on the surface of B- and T-lymphocytes. In recent years, it has become evident that endosomes and lysosomes are involved in many aspects of immune cell function, such as phagocytosis, antigen presentation and processing by antigen-presenting cells, release of proinflammatory mediators, e.g., by mast cells, or secretion of the pore-forming protein perforin by cytotoxic T lymphocytes. Several lysosomal storage disorders (LSDs) have been associated with defects in immune system function or immune system hyperactivity, such as Gaucher, Fabry, or Niemann-Pick type C1 disease, mucopolysaccharidoses (MPS), gangliosidosis, or juvenile neuronal ceroid lipofuscinosis (JNCL). Beside accumulating evidence on the importance of endolysosomes in immune cell function, recent results suggest direct roles of endolysosomal ion channels, such as the TRPML channels (mucolipins), which are members of the transient receptor potential (TRP) superfamily of non-selective cation channels, for different aspects of immune cell function. The aim of this review is to discuss the current knowledge about the roles of TRPML channels in inflammation and immunity, and to assess their potential as drug targets to influence immune cell functions.Advances: Examples of recently established roles of TRPML channels in immune system function and immune response include the TRPML1-mediated modulation of secretory lysosomes, granzyme B content, and tuning of effector function in NK cells, TRPML1-dependent directional dendritic cell (DC) migration and DC chemotaxis, and the role of TRPML2 in chemokine release from LPS-stimulated macrophages.Outlook: Although our understanding of the functional roles of TRPML channels in inflammation and immunity is still in its infancy, a few interesting findings have been made in the past years, encouraging further and more detailed work on the role of TRPMLs, e.g., in intracellular trafficking and release of chemokines, cytokines, or granzyme B, or in phagocytosis and bacterial toxin and virus trafficking through the endolysosomal machinery.

Cell Adhesion Molecules and Their Roles and Regulation in the Immune and Tumor Microenvironment.

The immune system and cancer have a complex relationship with the immune system playing a dual role in tumor development. The effector cells of the immune system can recognize and kill malignant cells while immune system-mediated inflammation can also promote tumor growth and regulatory cells suppress the anti-tumor responses. In the center of all anti-tumor responses is the ability of the immune cells to migrate to the tumor site and to interact with each other and with the malignant cells. Cell adhesion molecules including receptors of the immunoglobulin superfamily and integrins are of crucial importance in mediating these processes. Particularly integrins play a vital role in regulating all aspects of immune cell function including immune cell trafficking into tissues, effector cell activation and proliferation and the formation of the immunological synapse between immune cells or between immune cell and the target cell both during homeostasis and during inflammation and cancer. In this review we discuss the molecular mechanisms regulating integrin function and the role of integrins and other cell adhesion molecules in immune responses and in the tumor microenvironment. We also describe how malignant cells can utilize cell adhesion molecules to promote tumor growth and metastases and how these molecules could be targeted in cancer immunotherapy.

The Inhibition of Phosphoinositide-3 Kinases Induce Resolution of Inflammation in a Gout Model.

Phosphoinositide-3 kinases (PI3Ks) are central signaling enzymes that are involved in many aspects of immune cell function. PI3Kγ and PI3Kδ are the major isoforms expressed in leukocytes. The role of PI3K isoforms in the resolution of inflammation is still poorly understood. Here, we investigated the contribution of PI3Kγ and PI3Kδ to the resolution of inflammation in a model of gout in mice.Methods and Results: Experiments were performed in wild-type male C57/Bl6 mice. Selective inhibitors of PI3K-γ (AS605240) or PI3Kδ (GSK045) were injected in the joint 12 h after injection of MSU crystals, hence at the peak of inflammation. Inhibition of either PI3K isoform decreased number of neutrophils that migrated in response to the injection of MSU crystals. This was associated with reduction of myeloperoxidase activity and IL-1β levels in periarticular tissues and reduction of histological score. Joint dysfunction, as seen by reduced mechanical hypernociception, was improved by treatment with either inhibitor. The decrease in neutrophil numbers was associated with enhanced apoptosis and efferocytosis of these cells. There was shortening of resolution intervals, suggesting inhibition of either isoform induced the resolution of neutrophilic inflammation. Blockade of PI3Kγ or PI3Kδ reduced Nuclear Factor kappa B (NF-κB) activation. A pan-PI3K inhibitor (CL27c) reduced inflammation induced by MSU crystals by a magnitude that was similar to that attained by the PI3Kγ or PI3Kδ selective inhibitors alone.Conclusion: Taken together, these results suggest that neutrophils can use PI3Kγ or PI3Kδ to remain in the cavity and blockade of either isoenzyme is sufficient to induce their apoptosis and resolve inflammation in a murine model of gout.

β2 Integrins As Regulators of Dendritic Cell, Monocyte, and Macrophage Function.

Emerging evidence suggests that the β2 integrin family of adhesion molecules have an important role in suppressing immune activation and inflammation. β2 integrins are important adhesion and signaling molecules that are exclusively expressed on leukocytes. The four β2 integrins (CD11a, CD11b, CD11c, and CD11d paired with the β2 chain CD18) play important roles in regulating three key aspects of immune cell function: recruitment to sites of inflammation; cell–cell contact formation; and downstream effects on cellular signaling. Through these three processes, β2 integrins both contribute to and regulate immune responses. This review explores the pro- and anti-inflammatory effects of β2 integrins in monocytes, macrophages, and dendritic cells and how they influence the outcome of immune responses. We furthermore discuss how imbalances in β2 integrin function can have far-reaching effects on mounting appropriate immune responses, potentially influencing the development and progression of autoimmune and inflammatory diseases. Therapeutic targeting of β2 integrins, therefore, holds enormous potential in exploring treatment options for a variety of inflammatory conditions.

Regulation of Immune System Cell Functions by Protein Kinase C

Regulation of Immune System Cell Functions by Protein Kinase C

MicroRNA regulation of helper T cell cytokine production and proliferation (109.29)

Abstract MicroRNAs have been implicated as important regulators of many aspects of immune cell function. We and others have previously shown that deletion of the microRNA biogenesis enzymes Dicer and Drosha from T cells results in abnormal cytokine production and decreased proliferation of CD4+ T cells ex vivo. However, the role of individual miRNAs in this phenotype remains poorly understood. We conducted a screen for miRNA function in primary T cells and report the identification of individual miRNAs that can independently rescue the defects of miRNA-deficient helper T cells. Multiple members of the miR-17 and miR-92 families rescued proliferation while miR-29 rescued the aberrant IFN-γ expression by these cells. Repression of IFN-γ by miR-29 involved the regulation of both T-bet and Eomes, two transcription factors known to induce IFN-γ production. These results represent a novel screening strategy for miRNA function in primary T cells and further demonstrate the impressive regulatory capability of individual miRNAs in the immune system.

IL-17 and the Th17 lineage in systemic lupus erythematosus

Systemic lupus erythematosus etiology includes both genetic and environmental factors. Evidence suggests that many genetic loci in humans and mouse models contribute to the occurrence and clinical presentation of lupus. This large array of different genes affects many aspects of immune cell function, including the activation and functional differentiation of B cells, T cells, dendritic cells and other immune cells. In particular, the T-cell components that contribute to systemic lupus erythematosus pathogenesis are incompletely defined. A major paradigm shift in understanding how CD4+ T cells contribute to autoimmunity recently occurred with the discovery of a new T-cell population that produces the cytokine IL-17 (IL-17A), termed 'Th17'. Although Th17 cells contribute to autoimmune disease in rheumatoid arthritis and Crohn's disease, their role in systemic lupus erythematosus is far less clear. In this review, we focus on an emerging role for the cytokine IL-17 and the cells that produce it in contributing to lupus in particular based on recent findings in animal models.

Tachykinins in the Immune System

Until recently, the mammalian tachykinins included substance P, neurokinin A and neurokinin B. Following the discovery of the fourth member of this family, hemokinin 1, a diverse group of novel tachykinins and tachykinin gene-related peptides have been identified in mammals. These newly identified members are preferentially expressed in peripheral tissues. Currently, the impact of these new tachykinin peptides on the immune system remains unclear. Some data imply an important role for hemokinin 1 in the generation of lymphocytes. Tachykinins are traditionally viewed as neuropeptides with well-defined functions as neurotransmitters. Many studies however, indicate that they may also be produced by non-neuronal cells, and exert profound influence on inflammatory responses by affecting multiple aspects of immune cell function. It is of great importance to determine whether the new tachykinin peptides have similar effects. A more detailed understanding of the interactions between tachykinins and immune cells may provide the basis for the development of new therapies for inflammatory and immune-mediated diseases.

Differential effects of three antibiotics on T helper cell cytokine expression

To test whether ciprofloxacin, moxifloxacin and clarithromycin affect the expression of the T helper (Th) cell cytokines, interferon-gamma and interleukin-4. Quinolone and macrolide antibiotics are routinely used for the treatment of critically ill patients with sepsis. These antibiotics modulate some aspects of immune cell function. Alteration in the profile of Th cell cytokine expression will affect the T helper cell ratio and subsequent immune responses. Following ethics committee approval and informed consent, mononuclear cells were isolated from 20 healthy volunteers using single density gradient centrifugation. Cells were incubated with ciprofloxacin (0--100 mg/L), moxifloxacin (0--50 mg/L) or clarithromycin (0--125 mg/L) and stimulated with phorbol myristate acetate and ionomycin. For flow cytometric analysis, cells were stained with antibodies to CD3 and CD4, prior to permeabilization with saponin and intracellular staining with anti-interleukin-4 and anti-interferon-gamma. Both moxifloxacin and ciprofloxacin dose-dependently decreased interferon-gamma and interleukin-4 expression by Th cells (both P<0.0001). Only interleukin-4 expression however, was affected by clarithromycin (P=0.04). There was no change in the Th1/Th2 ratio for moxifloxacin or ciprofloxacin, but the Th1/Th2 ratio increased with increasing concentrations of clarithromycin, from a median [range] of 5.3 [1.3--16.0] without antibiotic to 9.1 [1.8--18.8] at 125 mg/L (P=0.017). Moxifloxacin and ciprofloxacin had pronounced effects on both Th1 and Th2 cytokine expression, without altering Th1/Th2 ratios. However, clarithromycin decreased only interleukin-4 expression such that the Th1/Th2 ratio increased. Since a Th1 profile is considered favourable for resolution of infection, elucidation of immunomodulatory profiles of antibiotics may permit more rational antibiotic choice in future.

Glutamine supplementation in vitro and in vivo, in exercise and in immunodepression.

In situations of stress, such as clinical trauma, starvation or prolonged, strenuous exercise, the concentration of glutamine in the blood is decreased, often substantially. In endurance athletes this decrease occurs concomitantly with relatively transient immunodepression. Glutamine is used as a fuel by some cells of the immune system. Provision of glutamine or a glutamine precursor, such as branched chain amino acids, has been seen to have a beneficial effect on gut function, on morbidity and mortality, and on some aspects of immune cell function in clinical studies. It has also been seen to decrease the self-reported incidence of illness in endurance athletes. So far, there is no firm evidence as to precisely which aspect of the immune system is affected by glutamine feeding during the transient immunodepression that occurs after prolonged, strenuous exercise. However, there is increasing evidence that neutrophils may be implicated. Other aspects of glutamine and glutamine supplementation are also addressed.

Semaphorin 4A Enhances T Cell Activation

Semaphorins, originally identified as axon guidance regulators in the nervous system, are also involved in various aspects of immune cell function (see Bismuth and Boumsell). Kumanagoh et al. report that Sema 4A enhanced T cell activation, measured as proliferation and stimulation of interleukin and interferon production, in vitro and in vivo. In a mouse model of autoimmune encephalomyelitis (EAE), EAE was suppressed if the mice were injected with an antibody against Sema 4A. The Tim-2 protein, a member of a family of proteins expressed on T cells that contain immunoglobulin and mucin domains, was identified by expression cloning as a receptor for Sema 4A. Unlike the CD100 (also known as Sema 4D), Sema 4A stimulated tyrosine phosphorylation of Tim-2 in transfected COS7 cells--CD100 promotes dephosphorylation of its receptor CD72. G. Bismuth, L. Boumsell, Controlling the immune system through semaphorins. Science's STKE (2002), http://stke.sciencemag.org/cgi/content/full/OC_sigtrans;2002/128/re4. [Abstract] [Full Text] A. Kumanogoh, S. Marukawa, K. Suzuki, N. Takegahara, C. Watanabe, E. Ch'ng, I. Ishida, H. Fujimura, S. Sakoda, K. Yoshida, H. Kikutani, Class IV semaphorin Sema4A enhances T-cell activation and interacts with Tim-2. Nature 419 , 629-633 (2002). [Online Journal]

X-linked lymphoproliferative disease

X-linked lymphoproliferative disease (XLP) is an inherited immune defect caused by germline mutations in SH2D1A (SH2 domain containing gene 1A; also known as DSHP, SAP), a gene that encodes a small adaptor protein expressed in T, NK, and some B cells. The clinical features of XLP are variable and include fulminant infectious mononucleosis, lymphoma, and hypogammaglobulinemia. Studies of the SH2D1A protein revealed important pathways regulating antiviral immunity. By interacting with specific cell-surface receptors, such as 2B4 (CD244), SLAM (CD150), and NTB-A, SH2D1A might regulate important aspects of immune cell function, including NK cell cytotoxicity, T-cell proliferation, and T H 1 cytokine secretion. Abnormalities in SH2D1A amino acid composition and protein expression levels seem to cause aberrant lymphocyte activation, contributing to the dysregulated immune response that characterizes XLP.