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Results for “Natural Killer T-Cells”

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At least 19 recordsLinked to original sources

PubMed2026

Integrative TWAS and multi-omics analyses prioritize HSPE1 as a candidate risk gene for bipolar disorder with immune cell-specific regulatory evidence.

BACKGROUND: Bipolar disorder (BD) is a severe psychiatric disorder associated with substantial disability. Although genome-wide association studies have identified multiple BD-associated loci, the underlying genes and mechanisms remain incompletely understood. METHODS: We integrated a European-ancestry BD genome-wide association dataset with cross-tissue and tissue-specific transcriptome-wide association studies (TWAS) and complementary gene-based analysis. Candidate genes were further evaluated using differential expression analysis, consensus clustering, immune infiltration analysis, machine learning, summary-data-based Mendelian randomization, Mendelian randomization using single-cell expression quantitative trait locus data, single-nucleus transcriptomics, phenome-wide association analysis, and virtual screening. RESULTS: The integrative analyses prioritized 37 candidate genes. Peripheral-blood differential-expression analysis identified 14 genes that remained significant after FDR correction, and their expression profiles separated BD samples into two expression-defined clusters. Machine-learning analysis selected UNC50, LMAN2L, LYG2, HSPE1, and KANSL3 for an exploratory classification nomogram. SMR associated genetically predicted higher HSPE1 expression with increased BD risk in two blood eQTL datasets. Cell-type-specific analyses indicated HSPE1-related associations in T-cell and natural killer cell subsets, while single-nucleus analysis descriptively showed higher HSPE1 expression in medial thalamic T cells from BD samples. PheWAS identified no genome-wide significant associations for HSPE1, whereas virtual screening identified candidate compounds with favorable predicted docking scores against the HSPE1 structure. CONCLUSION: This integrative multi-omics study identified HSPE1 as a candidate BD risk gene with immune-cell-related regulatory evidence, providing insight into BD pathogenesis and supporting functional validation.

Humans↗

PubMed2024

A comprehensive meta-analysis of tissue resident memory T cells and their roles in shaping immune microenvironment and patient prognosis in non-small cell lung cancer.

Tissue-resident memory T cells (TRM) are a specialized subset of long-lived memory T cells that reside in peripheral tissues. However, the impact of TRM-related immunosurveillance on the tumor-immune microenvironment (TIME) and tumor progression across various non-small-cell lung cancer (NSCLC) patient populations is yet to be elucidated. Our comprehensive analysis of multiple independent single-cell and bulk RNA-seq datasets of patient NSCLC samples generated reliable, unique TRM signatures, through which we inferred the abundance of TRM in NSCLC. We discovered that TRM abundance is consistently positively correlated with CD4+ T helper 1 cells, M1 macrophages, and resting dendritic cells in the TIME. In addition, TRM signatures are strongly associated with immune checkpoint and stimulatory genes and the prognosis of NSCLC patients. A TRM-based machine learning model to predict patient survival was validated and an 18-gene risk score was further developed to effectively stratify patients into low-risk and high-risk categories, wherein patients with high-risk scores had significantly lower overall survival than patients with low-risk. The prognostic value of the risk score was independently validated by the Cancer Genome Atlas Program (TCGA) dataset and multiple independent NSCLC patient datasets. Notably, low-risk NSCLC patients with higher TRM infiltration exhibited enhanced T-cell immunity, nature killer cell activation, and other TIME immune responses related pathways, indicating a more active immune profile benefitting from immunotherapy. However, the TRM signature revealed low TRM abundance and a lack of prognostic association among lung squamous cell carcinoma patients in contrast to adenocarcinoma, indicating that the two NSCLC subtypes are driven by distinct TIMEs. Altogether, this study provides valuable insights into the complex interactions between TRM and TIME and their impact on NSCLC patient prognosis. The development of a simplified 18-gene risk score provides a practical prognostic marker for risk stratification.

Humans↗

PubMed2026

Programmed cell death-1: from a T-cell immune checkpoint to a regulator of Natural Killer cell biology.

Programmed cell death protein 1 (PD-1, CD279) is a pivotal inhibitory immune checkpoint receptor that plays a central role in maintaining immune homeostasis and peripheral tolerance. Originally characterized as a negative regulator of T-cell activation, PD-1 limits excessive immune responses and prevents autoimmunity, while its sustained expression under conditions of chronic antigen stimulation contributes to T-cell dysfunction and exhaustion. The discovery that blockade of the PD-1 pathway can restore anti-tumor immunity has revolutionized cancer therapy and established immune checkpoint inhibition as a cornerstone of modern oncology. Although PD-1 has traditionally been viewed as a key regulator of adaptive immunity, accumulating evidence indicates that its biological functions extend beyond T cells. In recent years, PD-1 expression has been identified in several innate immune cell populations, particularly Natural Killer (NK) cells, where it has emerged as an important modulator of effector functions, cytokine production, metabolic fitness, and antitumor activity. These findings have challenged the classical view of PD-1 biology and revealed unexpected similarities between NK-cell dysfunction and the exhausted phenotype described in chronically stimulated T cells. In the tumor microenvironment, PD-1 expression on NK cells has been associated with impaired cytotoxicity and reduced immune surveillance, suggesting that NK cells may also represent relevant targets of PD-1-mediated immunosuppression. At the same time, the mechanisms regulating PD-1 expression and signaling in NK cells appear to differ, at least in part, from those operating in T lymphocytes, highlighting the complexity of this pathway across distinct immune cell subsets. In this review, we summarize the current knowledge of PD-1 biology, from its established role in T-cell regulation to its emerging functions in NK cells. We discuss the molecular mechanisms governing PD-1 expression and signaling, its contribution to immune dysfunction in cancer and chronic diseases, and the potential implications of targeting the PD-1 axis to enhance both adaptive and innate antitumor immunity.

Natural Killer (NK) cells↗

PubMed2026

Multiparametric flow cytometry immune profiling of pulmonary and extra-pulmonary tuberculosis reveals distinct blood-based biomarker signatures.

This study investigated immune cell distributions, cell-specific immune markers, and selected biomarker targets in pulmonary tuberculosis (PTB) and extrapulmonary tuberculosis (EPTB) using multiparametric flow cytometry (MFC). Whole blood was collected from 45 individuals, including healthy controls (HC), EPTB, and PTB patients (n = 15/group). Peripheral blood leukocytes were analysed by MFC to characterize CD4+ and CD8+ T cells, natural killer (NK), invariant NKT (iNKT) and NKT cells, classical (CM), intermediate (IM) and non-classical monocytes (NCM), and activated monocytes (AM). Expression of GBP1, CALCOCO2, IFIT3, SNX10, ARG1, PD-1, and PD-L1 was assessed across these immune subsets. Increased frequencies of NK, NKT, and monocytes were observed in PTB and EPTB compared with HC, while CD4+, CD8+, iNKT, and AM were reduced. Monocyte-to-lymphocyte ratios were incrementally elevated in EPTB and PTB compared with HC. Despite variability of expression within groups, median biomarker fold-change expression changes were found between HC, EPTB and PTB groups; (i) (>2.0FC) for ARG1 in CD4, CD8, CM and AM, for CALCOCO2 in AM, GBP1 in CD8 and NCM, PD-1 in CD4, CD8, NK, IM and AM, PD-L1 in CD4, CD8, iNKT and NKT, NK, IM and AM and SNX10 in CD4, CD8, NCM, IM and AM (ii) (<2.0FC) in TB vs HC for CALCOCO2 in iNKT and NKT, IFIT3 in NCM, PD-1 in NK and NCM, PD-L1 in NCM, IM and AM and SNX10 in AM. Statistical significance was achieved for ARG1 (P = 0.017) in CD4 cells. Our findings highlight distinct immune cell and biomarker signatures in PTB and EPTB.

Humans↗

PubMed2026

The role of Epstein-Barr virus in NK/T cell lymphoproliferative disorders: molecular mechanisms and potential therapeutic strategies.

Epstein-Barr virus (EBV) is a widely prevalent lymphotropic γ-herpesvirus, with approximately 95% of the population showing evidence of infection at some point during their lifetime. While most infections are asymptomatic or follow a self-limiting clinical course, in certain populations, EBV can lead to a range of lymphoproliferative disorders (LPDs), particularly subtypes originating from T cells and natural killer (NK) cells, which are often characterized by highly aggressive disease progression. This review aims to systematically discuss the molecular basis of EBV infection, covering its viral biological properties, regulation of the latent and lytic cycles, key viral protein functions (e.g., LMP1, LMP2A, EBNA1), miRNA regulatory mechanisms, and the activation of various host signaling pathways (such as NF-κB, PI3K-AKT, JAK-STAT) that contribute to the maintenance of latent infection, cell transformation, and immune evasion. Additionally, the review focuses on the pathogenic contributions of these mechanisms in EBV-related T/NK cell lymphoproliferative diseases. Research highlights include the in-depth analysis of virus-host genome interaction mechanisms, the identification of novel molecular biomarkers, and the development of targeted therapeutic strategies (e.g., PD-1/PD-L1 immune checkpoint inhibitors, EBV-specific T cell therapy). Through this comprehensive review, it is hoped that personalized medicine and artificial intelligence-assisted multimodal decision-making will be applied to the precise prevention and treatment of EBV-related diseases.

Humans↗

PubMed2026

A novel triple-knockout allogeneic BCMA CAR T-cell therapy (CT0590) for multiple myeloma: preclinical and phase 1 study.

Host-versus-graft reaction (HVGR) is a major challenge in allogeneic chimeric antigen receptor (CAR) T-cell therapy. To counter host natural killer (NK) cell attacks, we armored allogeneic, HLA-I-deficient, B-cell maturation antigen (BCMA)-targeting CAR T cells with an NKG2A CAR. In vitro and animal studies demonstrated that allogeneic CAR-NKG2A T cells effectively resisted host NK cell-mediated killing. BCMA and NKG2A dual-targeting allogeneic CAR T cells (CT0590) resisted killing by NK cells and showed robust antitumor activity in preclinical in vivo models. On the basis of these data, a first-in-human study enrolled 5 patients (4 with relapsed and refractory multiple myeloma [RRMM] and 1 with primary plasma cell leukemia [pPCL]). CT0590 was well tolerated and caused no dose-limiting toxicities, treatment-related death, or graft-versus-host disease. Three patients achieved confirmed responses, including 2 with stringent complete response (sCR). Notably, sCR in the patient with RRMM was still ongoing (duration of response >23 months) at the time of data cutoff, and sCR in the patient with pPCL lasted for 20 months. Both patients showed robust expansion of universal CAR T cells (maximum concentration of >280 000 copies per μg genomic DNA) and higher baseline NKG2A expression on NK cells than nonresponders. These results suggest that CAR-NKG2A technology may overcome HVGR, especially in patients with elevated NKG2A expression on NK cells. Further studies of CT0590 in RRMM and pPCL are warranted. This trial was registered at www.clinicaltrials.gov as NCT05066022.

Humans↗

PubMed1978

[Recognition of antigens by T-cells (author's transl)].

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Animals↗

PubMed2026

A novel FLNA p.Pro2469Ser variant is associated with impaired T and NK cell function and immune dysregulation.

FLNA encodes filamin A, a ubiquitously expressed actin-binding cytoskeletal protein that cross-links actin filaments and links them to membrane-associated signaling complexes. Although FLNA has been implicated in T-cell signaling and regulatory T-cell development in murine models, its role in human immune-cell function remains incompletely understood. Here, we investigated the immunological phenotype associated with a novel hemizygous FLNA variant identified in a pediatric patient presenting with recurrent infections and inflammatory manifestations. Whole-exome sequencing revealed a hemizygous c.7405C>T (p.Pro2469Ser) variant in FLNA, which was confirmed by Sanger sequencing. Its potential impact on immune-cell function and cytoskeletal organization was evaluated using confocal microscopy, flow cytometry, and molecular assays. Patient-derived T cells showed impaired activation and proliferation following CD3/CD28 and IL-2 stimulation, accompanied by reduced CD25 and CD69 upregulation. CD4+ T cells also exhibited reduced IFN-γ, TNF-α, and IL-2 production after stimulation. Despite elevated basal phospho-STAT5 levels, IL-2-induced STAT5 phosphorylation and TCR-associated signaling responses, including pZAP70, pLCK, and p38 MAPK activation, were attenuated. Confocal imaging together with image-based quantification demonstrated altered cortical cytoskeletal organization in patient T cells despite preserved FLNA expression. In parallel, NK cells showed impaired activation responses and reduced cytotoxic activity under the assay conditions used. Increased apoptosis was observed in CD4⁺, CD8⁺, and NK-cell populations. Inflammatory cytokines were elevated in plasma and colonic tissue, whereas colonic ZO-1 and FLNA expression were reduced. Collectively, these findings indicate that the FLNA p.Pro2469Ser variant is associated with altered immune-cell signaling, disturbed cortical cytoskeletal organization, and immune dysregulation. This study expands the phenotypic spectrum linked to FLNA variants and supports a role for filamin A in human immune-cell regulation.

Humans↗

PubMed1979

NK cell-sensitive T-cell subpopulation in thymus: inverse correlation to host NK activity.

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Aging↗

PubMed1979

Significance of the proline assay in the study of anti-MSV cell-mediated immune reactions.

The cytolysis of 3H-proline-labelled tumour cells growing in monolayer by syngeneic immune lymphocytes has been studied in the murine sarcoma virus (MSV) system. Results show that the proline assay (PA) is a convenient way to reveal the activity of cytolytic T lymphocytes against FMR-like antigens. Using the same effector and target cells, the classical chromium-release test (CRT) fails to reveal any cytolytic activity, and the visual microcytotoxicity assay as well as several derived isotopic methods are known to reveal mainly non-specific reactions due to non-T effector cells. The PA, therefore, appears to be a useful method for testing an antitumour reaction against tumour cells in monolayer. The results are, however, different from those obtained in the CRT using the same effector cells but lymphoma cells in suspension as targets, the major discrepancies being the following: (a) the PA does not provide truly quantitative data, due to the very high lymphoid: effector cell ratios needed in this test; (b) unexpected patterns of antigenic specificities are sometimes detected in PA; (c) a non-specific natural killer activity of non-T cells is frequently detected in the PA, masking at low lymphoid: target cell ratios the T-dependent specific cytolysis; (d) the H-2 restriction of the cytolytic T-cell activity is poorly detected in PA, whereas the role of H-2 antigens is clearly shown by blocking experiments using anti-H-2 antibodies.

Animals↗

PubMed2014

Jarid2 is induced by TCR signalling and controls iNKT cell maturation.

Jarid2 is a reported component of three lysine methyltransferase complexes, polycomb repressive complex 2 (PRC2) that methylates histone 3 lysine 27 (H3K27), and GLP-G9a and SETDB1 complexes that methylate H3K9. Here we show that Jarid2 is upregulated upon TCR stimulation and during positive selection in the thymus. Mice lacking Jarid2 in T cells display an increase in the frequency of IL-4-producing promyelocytic leukemia zinc finger (PLZF)(hi) immature invariant natural killer T (iNKT) cells and innate-like CD8(+) cells; Itk-deficient mice, which have a similar increase of innate-like CD8(+) cells, show blunted upregulation of Jarid2 during positive selection. Jarid2 binds to the Zbtb16 locus, which encodes PLZF, and thymocytes lacking Jarid2 show increased PLZF and decreased H3K9me3 levels. Jarid2-deficient iNKT cells perturb Th17 differentiation, leading to reduced Th17-driven autoimmune pathology. Our results establish Jarid2 as a novel player in iNKT cell maturation that regulates PLZF expression by modulating H3K9 methylation.

Animals↗

PubMed1979

Aberrations of suppressor T cells in human graft-versus-host disease.

To determine whether imbalances in immunoregulatory T-cell subsets exist in patients with graft-versus-host disease, we analyzed T cells in three patients with acute and in six patients with chronic graft-versus-host disease after bone-marrow transplantation. The normal human peripheral-blood T-cell compartment is composed of 80 per cent TH2-and 20 per cent TH2+ T cells, and defined by reactivity with subset-specific heteroantiserums. Human suppressor cells are TH2+, whereas helper cells are TH2-. Patients with acute and chronic graft-versus-host disease had abnormalities in these populations, and their T cells frequently bore la-like antigens. Patients with acute disease lacked TH2+ cells, and the reappearance of this subset preceded the cessation of disease activity. Chronic disease, in contrast, was more heterogeneous. Suppressor cells were lacking in two patients but increased in the other four. Two of these four patients had TH2+, la+ T cells, suggesting in vivo activation of suppressor cells. Studies showing that these TH2+, la+ cells actively suppressed the in vitro immune response support this hypothesis and suggest that the immunoregulatory cells may profoundly affect the overall immune response.

Acute Disease↗

PubMed1978

Suppressor T cells and suppressor factor.

The ability to suppress antibody response to specific antigens has been found to be inherent in a subpopulation of T lymphocytes. The suppressor pathway has been shown to involve an initial T-cell clone that that elaborates a soluble factor which, in turn, induces a second cohort of effector cells. The implications of this system for autoimmune and neoplastic diseases--and some relevant experiments--are discussed.

Animals↗

PubMed1978

Induction of specific immune unresponsiveness with purified mixed leukocyte culture-activated T lymphoblasts as autoimmunogen. III. Proof for the existence of autoanti-idiotypic killer T cells and transfer of suppression to normal syngeneic recipients by T or B lymphocytes.

Specific immune unresponsiveness against a given set of histocompatibility antigens can be induced by immunization with autologous, antigen-specific T lymphoblasts. Such unresponsiveness can be transferred by lymphoid cells from autoblast-immunized donors to normal syngeneic recipients. The cells being most efficient in transferring the selective suppression are T lymphocytes from the spleen, especially if of Ly 1-2+3+ phenotype. By using such T lymphocytes we deem it likely that the actual underlying mechanism is one of actual transfer of autoanti-idiotypic killer T cells. In support for this view is the fact that such T cells endowed with exquisite specific, cytolytic reactivity towards autologous idiotype-positive T target cells exist in autoblast immune animals. Significant suppression may also be transferred with T cells of Ly 1+2-3- phenotype or with B cells. Here, we consider the suppressive mechanism to be one of production of autoanti-idiotypic antibodies. By using affinity fraction procedures, it was finally possible to prove that all T-cell suppressive activity resides in a population with true antigen-binding-specific receptors for the relevant idiotypes.

Animals↗

PubMed1978

In a fully H-2 incompatible chimera, T cells of donor origin can respond to minor histocompatibility antigens in association with either donor or host H-2 type.

Fully H-2 incompatible radiation chimeras were prepared using BALB congenic mice. Such chimeric mice were immunized in vivo against histocompatibility antigens of the C57BL/10Sn (B10) background in association with either of the parental H-2 haplotypes, and their spleen cells subsequently boosted in vitro with the same minor antigens. Strong H-2-restricted cytotoxic activity against minor antigens was detected, and the specificity of the restriction could be to the H-2 haplotype of the donor or the host depending on the cells used for priming or boosting. Cross priming could also be demonstrated in these mice. The results show that fully allogenic radiation chimeras can produce H-2-restricted T-cell responses to minor histocompatibility (H) antigens, and are discussed in relation to contrasting results recently obtained against viral antigens.

Animals↗

PubMed1979

Idiotypic determinants on T-cell subpopulations.

Killer T cells with specificity for major histocompatibility antigens have been shown in mice and rats to display idiotypic receptors allowing the lysis of such cells at the effector phase by anti-idiotypic antibodies and complement. A comparison was made between idiotypes displayed by Lyt-1-2+3+ and Lyt-1+2-3- T blasts, generated in the same mixed leucocyte culture (MLC), across an entire H-2 locus barrier. This was done by absorption of anti-idiotypic antibodies with respective T blasts, followed by estimation of the ability of the absorbed antiserum to inhibit MLC or killer T-cell function. Further, the capacity of Lyt-purified, MLC-generated T blasts to provoke specific unresponsiveness via anti-idiotypic immunity in syngeneic recipients was analyzed. Taken together, the results demonstrate that Lyt-1+2-3- T blasts responsible for the major part of MLC proliferation have distincly different idiotypes from those on the Lyt 1-2+3+ killer T cells. That the idiotypes on the killer T-cell presursors can serve as triggering sites for induction of effector T-cell function was then suggested by experiments with Lyt-1-2+3+-purified, normal T cells as precursor cells in vitro. The fact that autoanti-idiotypic antibodies may circumvent the need for helper Lyt-1+2-3- T cells in the generation of allospecific killer T cells indicates that the former cells may normally function partly via such anti-idiotypic reactions.

Animals↗

PubMed1979

Mouse alloantibodies capable of blocking cytotoxic T-cell function. I. Relationship between the antigen reactive with blocking antibodies and the Lyt-2 locus.

In an attempt to produce allonatibodies to cytotoxic T-cell receptors, hyperimmune anti-lymphocyte antisera have been raised in mice of various strain combinations, and have been tested for their ability to block allogeneic cell-mediated lymphocytotoxicity (CML) in the absence of complement at the T killer cell level. Most of the sera failed to show any significant and reproducible inhibitory effects. However, among C3H anti-B10.BR antisera, some sera were found to be capable of significantly inhibiting CML. This effect was attributable to antibodies reacting with the killer population rather than the target cells, because the sera inhibited B10 anti-C3H CML but not C3H anti-b10 CML. Among mouse strains tested, A/J, BALB/c, B10, and B6 strains were sensitive to the inhibitory effect of the sera whereas AKR, CBA, C3H, and DBA/2 strains were insensitive. The sensitivity of killer cells to the inhibitory effect correlated well with the strain distribution of the Lyt-2.2 antigen. In the presence of complement, these same sera were toxic to 100% of spleen cells of AKR, BALB/c, B10, and DBA/2 strains, with comparable cytotoxic titers. Thus, the inhibitory activity of the sera could not be explained by nonspecific effects of high-titered antibodies. To study the relationship between the antigen(s) responsible for the blocking effect and Lyt-2-linked genes, killer cells from Lyt-2 congenic strains were tested and conventional anti-Lyt-2.2 antisera were raised in an appropriate congenic strain combination. Killer cells from B6, but not from B6.Ly2.1 animals, were significantly sensitive to the blocking effects of the inhibitory C3H anti-B10.BR sera. The conventional anti-Lyt.2.2 sera did produce CML blocking, although there was no apparent correlation between such blocking and the anti-Lyt-2.2 cytotoxic titer. These results thus indicate that the target molecules responsible for blocking of killer cells are encoded or regulated by genes that are closely linked to or identical with Lyt-2.

Animals↗

PubMed1979

Distinct Ir genes for helper and killer cells in the cytotoxic response to H-Y antigen.

The H-Y-specific cytotoxic T-cell response requires helper cells: cells from bone marrow chimeras B6 X CBA leads to B6, B6 X CBA leads to B10.A (5R), or B6 X CBA leads to CBA are each unable to respond to H-2k male cells. If, however, cells from B6 X CBA leads to B6 or B6 X CBA leads to B10.A (5R) chimeras are adoptively transferred together with cells from B6 X CBA leads to CBA chimeras, H-Y-specific CTL restricted to H-2k can be obtained. Thus, cells from B6 X CBA leads to B6 or B6 X CBA leads to B10.,A (5R) chimeras (restricted to the left end of the H-2b haplotype) can help CTL precursors from B6 X CBA leads to CBA chimeras (restricted to H-2k). The two classes of T cells required for the CTL response to H-Y antigen are controlled by different IR genes. All H-Y-specific CTL obtained from chimeras B6 + CBA leads to B6 X CBA were found to be of B6 origin. This suggests that CTL or their precursors must express antigens encoded in the left end of the H-2b haplotype for interaction with helper cells.

Animals↗