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Results for “Receptors, Interleukin-2”

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At least 19 recordsLinked to original sources

PubMed2024

Long noncoding RNA LIRIL2R modulates FOXP3 levels and suppressive function of human CD4+ regulatory T cells by regulating IL2RA.

Regulatory T cells (Tregs) are central in controlling immune responses, and dysregulation of their function can lead to autoimmune disorders or cancer. Despite extensive studies on Tregs, the basis of epigenetic regulation of human Treg development and function is incompletely understood. Long intergenic noncoding RNAs (lincRNA)s are important for shaping and maintaining the epigenetic landscape in different cell types. In this study, we identified a gene on the chromosome 6p25.3 locus, encoding a lincRNA, that was up-regulated during early differentiation of human Tregs. The lincRNA regulated the expression of interleukin-2 receptor alpha (IL2RA), and we named it the lincRNA regulator of IL2RA (LIRIL2R). Through transcriptomics, epigenomics, and proteomics analysis of LIRIL2R-deficient Tregs, coupled with global profiling of LIRIL2R binding sites using chromatin isolation by RNA purification, followed by sequencing, we identified IL2RA as a target of LIRIL2R. This nuclear lincRNA binds upstream of the IL2RA locus and regulates its epigenetic landscape and transcription. CRISPR-mediated deletion of the LIRIL2R-bound region at the IL2RA locus resulted in reduced IL2RA expression. Notably, LIRIL2R deficiency led to reduced expression of Treg-signature genes (e.g., FOXP3, CTLA4, and PDCD1), upregulation of genes associated with effector T cells (e.g., SATB1 and GATA3), and loss of Treg-mediated suppression.

Humans↗

PubMed1992

Evaluation of soluble CD 14 and neopterin as serum parameters of the inflammatory activity of pulmonary sarcoidosis.

CD14 represents the most specific marker for monocytes/macrophages. It has been demonstrated in vitro that monocytes/macrophages lose this antigen upon activation. Results of studies investigating the expression of membrane-bound CD14 on the surface of monocytes/macrophages in sarcoidosis patients are controversial. To investigate whether the soluble form of CD14 reflects monocyte/macrophage activation in sarcoidosis, serum levels of soluble CD14 were determined concurrently with other serum markers of monocyte/macrophage activation (neopterin, angiotensin-converting enzyme) in 50 consecutive patients with bioptically confirmed sarcoidosis. The patients were allocated to three groups according to disease activity and therapy. The soluble interleukin-2 receptor in serum and the CD4/CD8 ratio in lavage fluid were used to monitor T-lymphocyte activation. No significant differences in serum or bronchoalveolar lavage levels of soluble CD14 were observed in patients with active or inactive sarcoidosis. Despite the presence of normal soluble CD14 serum concentrations a correlation with serum neopterin and angiotensin-converting enzyme was found in active sarcoidosis (soluble CD14 versus neopterin, rs = 0.61 and 0.65, P < 0.05 and 0.01, respectively; soluble CD14 versus angiotensin-converting enzyme, rs = 0.6 and 0.72, P < 0.02 and 0.003, respectively). A correlation between soluble CD14 and parameters of T-cell activity was not demonstrated. We therefore conclude that soluble CD14 in serum is not a useful clinical parameter in establishing disease activity in sarcoidosis. Neopterin and angiotensin-converting enzyme serum concentrations are parameters with higher sensitivity, although specificity remains very low. The exact role of CD14 antigen in sarcoidosis requires further investigation.

Antigens, CD↗

PubMed1992

An unusual T-cell surface phenotype in vivo correlates with the failure to proliferate and produce IL-2 in vitro in a patient with common variable immunodeficiency.

Stimulation of T-lymphocytes derived from some patients with common variable immunodeficiency (CVID) syndrome results in defective proliferation. The underlying mechanism is related to the inability of stimulated cells to secrete IL-2 while the expression of IL-2 receptor (IL-2R) is normal. We have identified a patient whose peripheral T-cells failed to proliferate and secrete IL-2 upon stimulation. The addition of recombinant IL-2 restored proliferation. The defect did not seem to be caused by accessory cell failure since the patient's adherent cells produced IL-1 and IL-6, and addition of allogeneic irradiated cells did not induce proliferation. Stimulation of CVID T-cells with phorbol esters and Ca2+ ionophore induced both IL-2 secretion and proliferation, indicating the absence of a defect in the transcription and/or translation of the IL-2 gene. The patient's T-cells expressed high levels of CD3. The majority of T-cells expressed the CD38 molecule which is normally found on thymocytes or activated T-cells but not peripheral blood T-cells and HLA-DR, another activation marker. However, CD25 (the IL-2R) and CD1, a marker of more immature thymocytes, were not expressed. Finally, the patient's cells were sensitive to an in vitro corticosteroid treatment. The possibilities that this patient's T-cells represent anergic T-cells or not fully matured thymocytes are discussed.

ADP-ribosyl Cyclase↗

PubMed2024

Regulating IL-2 Immune Signaling Function Via A Core Allosteric Structural Network.

Human interleukin-2 (IL-2) is a crucial cytokine for T cell regulation, with therapeutic potential in cancer and autoimmune diseases. However, IL-2's pleiotropic effects across different immune cell types often lead to toxicity and limited efficacy. Previous efforts to enhance IL-2's therapeutic profile have focused on modifying its receptor binding sites. Yet, the underlying dynamics and intramolecular networks contributing to IL-2 receptor recognition remain unexplored. This study presents a detailed characterization of IL-2 dynamics compared to two engineered IL-2 mutants, "superkines" S15 and S1, which exhibit biased signaling towards effector T cells. Using NMR spectroscopy and molecular dynamics simulations, we demonstrate significant variations in core dynamic pathways and conformational exchange rates across these three IL-2 variants. We identify distinct allosteric networks and minor state conformations in the superkines, despite their structural similarity to wild-type IL-2. Furthermore, we rationally design a mutation (L56A) in the S1 superkine's core network, which partially reverts its dynamics, receptor binding affinity, and T cell signaling behavior towards that of wild-type IL-2. Our results reveal that IL-2 superkine core dynamics play a critical role in their enhanced receptor binding and function, suggesting that modulating IL-2 dynamics and core allostery represents an untapped approach for designing immunotherapies with improved immune cell selectivity profiles.

Interleukin-2↗

PubMed2025

Well-differentiated systemic mastocytosis: Genetics, mast cell immunophenotypes, and KIT autophosphorylation.

BACKGROUND: Well-differentiated systemic mastocytosis (WDSM) is a rare myeloid neoplasm where the genetic etiology is often unknown. OBJECTIVE: We aimed to assess WDSM patients for novel KIT variants, mast cell (MC) aberrant immunophenotypes, and KIT autophosphorylation patterns. METHODS: Next-generation sequencing, MC immunophenotyping, and KIT autophosphorylation studies were performed. RESULTS: Among 454 SM patients, there were 432 with KIT p.D816V+ SM and 4 with KIT p.D816Y+ SM-notably, none of these patients had WDSM. Of the remaining patients, we identified 7 with WDSM (1.5%) and 2 relatives with mastocytosis in skin. Next-generation sequencing revealed that 6 of 9 subjects carried known or novel germline KIT variants corresponding to regions outside of codon 816. Three patients had germline KIT p.K509I; 2 had germline KIT p.A533D; 1 had two germline KIT variants p.F681L and p.M541L; and 3 had no KIT mutation. Intracellular expression of CD2 and CD25 and less robust expression of CD30 was observed in MCs from WDSM patients. By developing a novel transient transfection assay in 293T cells, we found that unlike KIT p.D816F/V/Y variants that exhibit nearly exclusive intracellular localization and strong ligand-independent autophosphorylation (class II), WDSM-associated KIT variants showed enhanced ligand-dependent autophosphorylation relative to wild type (class I). CONCLUSIONS: Our study doubles the number of KIT variants identified in WDSM patients. No KIT p.D816V+ SM patient had WDSM. Intracellular CD2 and CD25 expression was more robustly detected in MCs from WDSM patients compared to CD30.

Humans↗

PubMed2013

MicroRNA-directed program of cytotoxic CD8+ T-cell differentiation.

Acquisition of effector properties is a key step in the generation of cytotoxic T lymphocytes (CTLs). Here we show that inflammatory signals regulate Dicer expression in CTLs, and that deletion or depletion of Dicer in mouse or human activated CD8(+) T cells causes up-regulation of perforin, granzymes, and effector cytokines. Genome-wide analysis of microRNA (miR, miRNA) changes induced by exposure of differentiating CTLs to IL-2 and inflammatory signals identifies miR-139 and miR-150 as components of an miRNA network that controls perforin, eomesodermin, and IL-2Rα expression in differentiating CTLs and whose activity is modulated by IL-2, inflammation, and antigenic stimulation. Overall, our data show that strong IL-2R and inflammatory signals act through Dicer and miRNAs to control the cytolytic program and other aspects of effector CTL differentiation.

Adoptive Transfer↗

PubMed1992

Activation of human peripheral blood T lymphocytes by pharmacological induction of protein-tyrosine phosphorylation.

Protein-tyrosine kinase and protein-tyrosine phosphatase (PTPase) activities are essential for T-cell antigen receptor-mediated signaling. To assess the functional consequences of alteration of the levels of tyrosine phosphorylation in normal human T cells, the effects of vanadate and hydrogen peroxide were studied. In combination, these agents induced tyrosine phosphorylation of cellular substrates, elevated cytosolic free calcium, and induced interleukin 2 receptor (IL-2R) alpha chain expression but not IL-2 secretion. However, anti-CD28 antibody in combination with vanadate and hydrogen peroxide induced IL-2 secretion, consistent with the requirement for a costimulatory signal in the induction of this gene. The effects of vanadate and hydrogen peroxide were enhanced in the absence of the T-cell PTPase, CD45. Thus, acute pharmacologic manipulation of the level of tyrosine phosphorylation in normal T cells correlates with partial, but not full, activation of these cells; in concert with a costimulatory signal provided by perturbation of the CD28 molecule, the complete program of activation is initiated. These agents should prove useful in dissecting signaling pathways involved in the regulation of genes critical to the immune response.

Animals↗

PubMed2026

Stage-specific ROMO1 in rheumatoid arthritis: predictive immune insights into the MIF pathway and HLA-DR/IL2RA axis via integrated GWAS, transcriptomic, single-cell, and spatial profiling.

Emerging evidence links reactive oxygen species modulator 1 (ROMO1), a key mitochondrial ROS regulator, to rheumatoid arthritis (RA) pathogenesis. However, its exact mechanism remains elusive given the conflicting evidence about its specific function. We used a four-level integrative framework combining multi-omics data and literature‑supported mechanistic inference. At the genetic level, Mendelian randomization (MR) was performed to explore potential causal relationships between ROMO1, IL2RA, HLA-DR, MIF, and RA risk, followed by differential expression analysis and machine learning-based feature selection to identify key mROS genes. The temporal expression dynamics of ROMO1 were assessed in RA progression. At the cellular and tissue levels, we integrated single-cell RNA sequencing and spatial transcriptomics to map cell-type-specific expression and synovial localization of ROMO1-related immune cells and pathways. Finally, our multi-omics findings were contextualized with literature-supported mechanistic inference. (1) MR results were consistent with a potential protective effect of ROMO1 on RA (OR = 0.52) and its potential regulation of risk factors IL2RA (OR = 0.46) and HLA-DR (OR = 0.40). Conversely, IL2RA (OR = 1.42), HLA-DR (OR = 1.88), and MIF (OR = 1.17) were positively associated with RA risk. Additionally, ROMO1 was identified as a top candidate diagnostic predictor with stage-specific dynamics: downregulated in the early but upregulated in the late/remission stages. (2) Single-cell RNA sequencing showed ROMO1's cell-specific expression in CD14+ HLA-DR+ CD74+ monocytes and CD4+ IL2RA+ T cells. Cell communication analysis further suggested that these cells may participate in MIF pathway regulation. Spatial transcriptomics subsequently identified that ROMO1-related cells localized to synovial pathological regions, with MIF pathway changes correlated with RA progression. (3) Finally, literature-supported mechanistic inference suggests that ROMO1 may modulate mROS levels to promote anti-inflammatory M2 macrophage polarization, which could theoretically contribute to reduced systemic inflammation and the alleviation of multi-organ decline in RA. This integrated multi-omics investigation, supported by literature-based mechanistic inference, suggests ROMO1 as a stage-dependent biomarker candidate and potential immune regulator in RA.

Humans↗

PubMed2026

Role of CD25hi CD45RA+ CD4 not Treg %T cell in mediating the effect of pyruvate fermentation to acetone on intrahepatic cholangiocarcinoma.

This study aimed to elucidate the potential correlation between gut microbiota and intrahepatic cholangiocarcinoma (ICC) by investigating their causal relationship, while also exploring the possible role of immune cells as mediators in this association. We first identified gut microbiota based on phylum, class, order, family, and genus level information. Using summary-level data from a Genome-Wide Association Study (GWAS), we performed a 2-sample Mendelian randomization (MR) analysis of ICC and gut microbiota. Furthermore, we used 2-step MR to quantify the proportion of the effect of immune cell-mediated gut microbiota on ICC. MR analysis identified pyruvate fermentation to acetone (PFA) as predicting ICC risk reduction. There was no strong evidence that genetically predicted ICC had an effect on PFA risk. Furthermore, the proportion of genetically predicted PFA mediated by CD25hi CD45RA+ CD4 not Treg %T cell (CCCTT) was 3% (95% CI: 0.93-5.03%). In conclusion, our study established a causal relationship between PFA and ICC. We observed that a minor fraction of this effect was mediated by CCCTT, while the majority of the impact exerted by PFA on ICC remains elusive. However, further investigations are warranted to elucidate the mechanisms underlying the influence of gut microbiota on ICC development.

Cholangiocarcinoma↗

PubMed2024

Class IIa HDAC4 and HDAC7 cooperatively regulate gene transcription in Th17 cell differentiation.

Class II histone deacetylases (HDACs) are important in regulation of gene transcription during T cell development. However, our understanding of their cell-specific functions is limited. In this study, we reveal that class IIa Hdac4 and Hdac7 (Hdac4/7) are selectively induced in transcription, guiding the lineage-specific differentiation of mouse T-helper 17 (Th17) cells from naive CD4+ T cells. Importantly, Hdac4/7 are functionally dispensable in other Th subtypes. Mechanistically, Hdac4 interacts with the transcription factor (TF) JunB, facilitating the transcriptional activation of Th17 signature genes such as Il17a/f. Conversely, Hdac7 collaborates with the TF Aiolos and Smrt/Ncor1-Hdac3 corepressors to repress transcription of Th17 negative regulators, including Il2, in Th17 cell differentiation. Inhibiting Hdac4/7 through pharmacological or genetic methods effectively mitigates Th17 cell-mediated intestinal inflammation in a colitis mouse model. Our study uncovers molecular mechanisms where HDAC4 and HDAC7 function distinctively yet cooperatively in regulating ordered gene transcription during Th17 cell differentiation. These findings suggest a potential therapeutic strategy of targeting HDAC4/7 for treating Th17-related inflammatory diseases, such as ulcerative colitis.

Animals↗

PubMed1979

The role of p23,30-bearing human macrophages in antigen-induced T lymphocyte responses.

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Animals↗

PubMed2026

Natural killer (NK) cells with downregulated activating receptors and IL-10 production promote Trypanosoma cruzi T-cell responses in subjects in the Chronic phase of Trypanosoma cruzi infection: An exploratory immunological analysis.

BACKGROUND: Subjects with chronic Chagas disease and no signs of heart disease exhibit decreased NKp46 expression, high CD57 expression, and IL-10 production by NK cells. This study provides a detailed characterization of the phenotype and function of NK cells according to the severity of heart disease, and evaluates how these changes following treatment with benznidazole, as well as their association with Trypanosoma cruzi-specific T-cell responses. METHODS: The phenotype and function of NK cells in a cohort of 51 subjects infected with Trypanosoma cruzi and exhibiting varying degrees of heart disease were evaluated using high-dimensional flow cytometry and Boolean gating analysis. ELISPOT assays were performed to measure IFN-γ and IL-2 production in response to T. cruzi antigens, using CD56, CD4 and CD8-depleted PBMC. RESULTS: In contrast to individuals without heart disease, those with advanced cardiomyopathy have an increased number of NK cells that express the activating receptors NKp46 and CD16, as well as the differentiation marker CD57. NK cells in subjects with advanced cardiomyopathy were also found to be enriched in CD56+CD107+granzyme B+TNF-α+ cells and depleted of CD56+IL-10+ cells. The function of NK cells shifted towards monofunctionality in subjects with declining T. cruzi-specific antibodies following treatment with benznidazole. Eliminating CD56+ cells significantly decreased the number of IFN-γ-producing cells in response to T. cruzi. CONCLUSIONS: In chronic T. cruzi infection, NK-cell function may be balanced by the downregulation of activating receptors and IL-10 production, However, parasite persistence may desensitize the regulation of NK activating receptors, enabling NK cells to exert a potent polyfunctional cytotoxicity that potentially induce tissue damage.

Humans↗

PubMed1992

Selective endothelial binding of interleukin-2-dependent human T-cell lines derived from different tissues.

The ability of lymphocytes to recognize and bind to high endothelial venules (HEVs) is essential for lymphocyte migration from the blood into lymphoid tissues and into sites of inflammation. Endothelial cell binding capacity also critically determines the clinical usefulness of T-cell lines and clones in immunotherapy. In the present study, interleukin-2-dependent T-cell lines were derived from the blood, lamina propria of the gut, inflamed synovium, synovial fluid, and peripheral lymph nodes. After 3-8 weeks of culture, the expression of homing-associated molecules and binding to mucosal, synovial, and peripheral lymph node HEVs were analyzed. Cell lines derived from the blood and mucosal sites bound significantly better to mucosal and synovial HEVs than to peripheral lymph node HEVs. Three out of seven synovial T-cell lines showed preferential binding to synovial HEVs, whereas the rest bound almost equally well to synovial and mucosal HEVs. T-cell lines from peripheral lymph nodes bound preferentially to lymph node HEVs despite the lack of L-selectin (the peripheral lymph node homing receptor). Expression of the known homing-associated molecules did not predict the HEV-binding specificity of these lines. Importantly, two cell lines bound well to synovial venules, but poorly, if at all, to mucosal or peripheral lymph node HEVs, supporting the concept that synovial-specific HEV recognition mechanisms exist. In conclusion, the tissue origin of T-cell lines critically determines their selectivity for endothelial cell recognition, and besides the known "homing receptors," other molecules may also mediate tissue-specific HEV-binding of interleukin-2-activated T cells.

Antigens, CD↗

PubMed1979

The in vitro effects of Bordetella pertussis lymphocytosis-promoting factor on murine lymphocytes. III. B-cell dependence for T-cell proliferation.

The nature of the helper lymphocytes in lymphocytosis-promoting factor (LPF)-induced proliferation was explored. Removal of macrophages from adherent splenocytes by either carbonyl-iron incubation or passage through Sephadex G-10 columns did not affect their synergistic function. Nor did cytolysis with Thy-1.2 antiserum and complement. The helper cells were found to be surface immunoglobulin-positive (sIg+) because they are retained by anti-Ig columns, susceptible to lysis by rabbit anti-mouse immunoglobulin and complement, and occurred in the sIg+ fractions of splenocytes after separation on the fluorescence-activated cell sorter. Further delineation of the surface markers on helper cells showed that complement receptors are not the determining marker for synergistic function. The requirement for B-helper cells in the stimulation of T lymphocytes by LPF is unique for a mouse of T-cell mitogen.

Animals↗

PubMed2026

TGF-β and IL-2 differentially shape T follicular regulatory cell differentiation and stability in vitro.

T follicular helper (Tfh) cells and T follicular regulatory (Tfr) cells play critical roles in regulating the activity of the germinal center (GC), which is essential for the generation of high-affinity antibodies. In the GC, Tfh cells help B cells to proliferate and to differentiate into memory B cells and long-lived plasma cells. In contrast, Tfr cells, a specialized subset of regulatory T cells (Tregs), modulate the humoral immune response by suppressing excessive or autoreactive B-cell activity. Here, we established an in vitro differentiation protocol for mouse CD4⁺ T cells that yielded CXCR5⁺FoxP3⁺ Tfr cells that exhibited a Bcl6hiPD-1hiCD25loGITRint phenotype and were distinct from Treg and Tfh cells. Functionally, in vitro-generated Tfr cells potently suppressed Tfh cell-driven B-cell class switching to IgG1 and downregulated the expression of B-cell costimulatory ligands. While in vitro-generated Bcl6-deficient Tfh cells were impaired in providing help to B cells for efficient class switching to IgG1, in vitro-generated Bcl6-deficient Tfr cells failed to inhibit Tfh cell-driven B-cell class switching to IgG1. Mechanistically, we showed that Tfr cells emerged from FoxP3+ precursors in low-IL-2 environments through a TGF-β- and c-Maf-dependent pathway, allowing for reprogramming and reinforcement of the follicular regulatory cell program in CD4+ T cells in vitro.

Animals↗

PubMed1979

Characterization of lymphocytes which inhibit proliferation of human T cells exposed to lymphocyte-derived mitogenic factors.

Culture supernatants of PHA-activated human lymphocytes (active SUPs) contain factors which are strongly mitogenic for fractionated peripheral T cells. This stimulation is suppressed by certain non-T lymphocytes. It is shown that these suppressor cells can inhibit an ongoing response of T cells to active SUP and that this inhibition is reversible. Using various rosette sedimentation techniques for fractionating subpopulations of lymphocytes it is concluded that the suppressor cells lack membrane-associated receptors for C3 but possess receptors for the Fc part of IgG. This subset of lymphocytes may be an important regulator of lymphocyte proliferation during immune responses.

Adult↗

PubMed1992

The immune system and gynaecological cancer.

There have been major advances in our understanding of the cellular and humoral immune mechanisms involved in antitumour activities. The characterization of soluble mediators of the immune response and their synthesis as recombinant proteins has led to an explosion of research activity concerning their role as antitumour agents and also as contributors to the pathogenesis of cancer. It is evident that cytokine production is not restricted to cells of the immune system, and that cytokines are involved in a variety of cell regulatory processes ranging from embryonic development to tissue differentiation. Their production by immune cells may enable interactions between the immune system and other homeostatic systems of the body. The therapeutic role of some cytokines such as the interferons and IL-2 in the routine management of gynaecological cancers needs to be investigated further because of their promise as antitumour agents. The study of cytokine production and cytokine receptor expression by cancers is potentially of great therapeutic value. Identification of cytokines that contribute to tumour progression may paradoxically lead to the treatment of cancers by agents that antagonize their biological effects and to rationalization of future trials of cytokine therapy.

Cytokines↗

PubMed1992

CD4-independent inhibition of lymphocyte proliferation mediated by HIV-1 envelope glycoproteins.

The cytopathic effects of HIV-1 produced by direct infection of human T cells do not account for the disproportionate loss of CD4-positive lymphocytes during the course of HIV infection. Previous studies have demonstrated the inhibition of uninfected human T cell activation and proliferation by the HIV-1 envelope glycoproteins, presumably due to gp120-CD4 interactions. To examine the ability of HIV-1 to inhibit T cell proliferation in the absence of both direct infection and gp120-CD4 interactions, we tested the effect of HIV-1 on mouse T cell proliferation. Culture media containing HIV-1 released from infected cells inhibited T lymphocyte proliferation in response to interleukin-2 (IL-2). Studies to explore the mechanism of this inhibition suggested that the decrease in proliferation resulted from interactions between HIV-1 and the mouse cells, but did not involve IL-2/IL-2 receptor interactions. We used monoclonal antibodies to demonstrate that the HIV-1 envelope glycoproteins were required for the inhibition of murine T cell proliferation. Anti-gp120 antibodies completely restored proliferation, indicating that the surface protein gp120 was primarily required for the inhibition of proliferation. However, antibodies directed against the transmembrane protein of HIV-1 (gp41) also partially restored lymphocyte proliferation. The functional significance of the HIV-1 envelope protein epitopes recognized by the monoclonal antibodies is discussed.

Animals↗