ABSTRACT
The balance of proinflammatory T helper type 17 (TH17) and anti-inflammatory T regulatory (Treg) cells is crucial for immune homeostasis in health and disease. The differentiation of naïve CD4+ T cells into TH17 and Treg cells depends on T cell receptor (TCR) signaling mediated, in part, by interleukin-2-inducible T cell kinase (ITK), which stimulates mitogen-activated protein kinases (MAPKs) and Ca2+ signaling. Here, we report that, in the absence of ITK activity, naïve murine CD4+ T cells cultured under TH17-inducing conditions expressed the Treg transcription factor Foxp3 and did not develop into TH17 cells. Furthermore, ITK inhibition in vivo during allergic inflammation increased the Treg:TH17 ratio in the lung. These switched Foxp3+ Treg-like cells had suppressive function, and their transcriptomic profile resembled that of differentiated, induced Treg (iTreg) cells, but their chromatin accessibility profiles were intermediate between TH17 and iTreg cells. Like iTreg cells, switched Foxp3+ Treg-like cells had reductions in the expression of genes involved in mitochondrial oxidative phosphorylation and glycolysis, in the activation of the mechanistic target of rapamycin (mTOR) signaling pathway, and in the abundance of the TH17 pioneer transcription factor BATF. This ITK-dependent switch between TH17 and Treg cells depended on Ca2+ signaling but not on MAPKs. These findings suggest potential strategies for fine-tuning TCR signal strength through ITK to control the balance of TH17 and Treg cells.
Subject(s)
Cell Differentiation , Forkhead Transcription Factors , Protein-Tyrosine Kinases , T-Lymphocytes, Regulatory , Th17 Cells , Animals , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/cytology , T-Lymphocytes, Regulatory/metabolism , Th17 Cells/immunology , Th17 Cells/cytology , Th17 Cells/metabolism , Mice , Forkhead Transcription Factors/metabolism , Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/immunology , Protein-Tyrosine Kinases/metabolism , Protein-Tyrosine Kinases/genetics , Protein-Tyrosine Kinases/immunology , Calcium Signaling , Mice, Inbred C57BL , Calcium/metabolism , Mice, Knockout , TOR Serine-Threonine Kinases/metabolism , TOR Serine-Threonine Kinases/immunologyABSTRACT
Regulatory T (Treg) cells play a key role in maintaining immune tolerance and tissue homeostasis. However, in some disease microenvironments, Treg cells exhibit fragility, which manifests as preserved FoxP3 expression accompanied by inflammation and loss of immunosuppression. Fragile Treg cells are formatively, phenotypically and functionally diverse in various diseases, further complicating the role of Treg cells in the immunotherapeutic response and offering novel targets for disease treatment by modulating specific Treg subsets. In this review, we summarize findings on fragile Treg cells to provide a framework for characterizing the formation and role of fragile Treg cells in different diseases, and we discuss how this information may guide the development of more specific Treg-targeted immunotherapies.
Subject(s)
Homeostasis , T-Lymphocytes, Regulatory , Humans , T-Lymphocytes, Regulatory/immunology , Animals , Homeostasis/immunology , Forkhead Transcription Factors/metabolism , Forkhead Transcription Factors/immunology , ImmunotherapyABSTRACT
Background: IL-35 potently inhibits immune responses both in vivo and in vitro. However, the specific characteristics of IL-35-producing cells, including their developmental origin, cellular phenotype, and function, are unknown. Methods: By using a novel IL-35 reporter mouse (Ebi3-Dre-Thy1.1) and double transgenic fate-mapping reporter mice (35EbiT-Rosa26-rox-tdTomato reporter mice or Foxp3 fate-mapping system), we tracked and analyzed the differentiation and developmental trajectories of Tr35 cells in vivo. And then we investigated the therapeutic effects of OVA-specific Tr35 cells in an OVA-induced allergic airway disease model. Results: We identified a subset of cells, denoted Tr35 cells, that secrete IL-35 but do not express Foxp3. These cells have high expression of molecules associated with T-cell activation and can inhibit T-cell proliferation in vitro. Our analyses showed that Tr35 cells are a distinct subpopulation of cells that are independent of Tr1 cells. Tr35 cells exhibit a unique gene expression profile and tissue distribution. The presence of Thy1.1 (Ebi3) expression in Tr35 cells indicates their active secretion of IL-35. However, the proportion of ex-Tr35 cells (Thy1.1-) is significantly higher compared to Tr35 cells (Thy1.1+). This suggests that Tr35 cells possess the ability to regulate IL-35 expression rapidly in vivo. Tr35 cells downregulated the expression of the inflammatory cytokines IL-4, IFN-γ and IL-17A. However, once Tr35 cells lost IL-35 expression and became exTr35 cells, the expression of inflammatory cytokines was upregulated. Importantly, our findings indicate that Tr35 cells have therapeutic potential. In an OVA-induced allergic airway disease mouse model, Tr35 cell reinfusion significantly reduced airway hyperresponsiveness and histopathological airway and lung inflammation. Conclusions: We have identified a subset of Tregs, Tr35 cells, that are distinct from Tr1 cells. Tr35 cells can dynamically regulate the secretion of inflammatory cytokines by controlling IL-35 expression to regulate inflammatory immune responses.
Subject(s)
Cell Plasticity , Interleukins , T-Lymphocytes, Regulatory , Animals , Female , Mice , Cell Differentiation , Cell Proliferation , Disease Models, Animal , Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/immunology , Interleukins/genetics , Interleukins/immunology , Lymphocyte Activation , Mice, Inbred C57BL , Mice, Transgenic , Ovalbumin/immunology , T-Lymphocytes, Regulatory/immunologyABSTRACT
Lung macrophages constitute a sophisticated surveillance and defense system that contributes to tissue homeostasis and host defense and allows the host to cope with the myriad of insults and antigens to which the lung mucosa is exposed. As opposed to alveolar macrophages, lung interstitial macrophages (IMs) express high levels of Type 2 major histocompatibility complex (MHC-II), a hallmark of antigen-presenting cells. Here, we showed that lung IMs, like dendritic cells, possess the machinery to present soluble antigens in an MHC-II-restricted way. Using ex vivo ovalbumin (OVA)-specific T cell proliferation assays, we found that OVA-pulsed IMs could trigger OVA-specific CD4+ T cell proliferation and Foxp3 expression through MHC-II-, IL-10-, and transforming growth factor ß-dependent mechanisms. Moreover, we showed that IMs efficiently captured locally instilled antigens in vivo, did not migrate to the draining lymph nodes, and enhanced local interactions with CD4+ T cells in a model of OVA-induced allergic asthma. These results support that IMs can present antigens to CD4+ T cells and trigger regulatory T cells, which might attenuate lung immune responses and have functional consequences for lung immunity and T cell-mediated disorders.
Subject(s)
Antigen Presentation , Asthma , Forkhead Transcription Factors , Lung , Ovalbumin , T-Lymphocytes, Regulatory , Animals , T-Lymphocytes, Regulatory/immunology , Forkhead Transcription Factors/metabolism , Forkhead Transcription Factors/immunology , Ovalbumin/immunology , Lung/immunology , Antigen Presentation/immunology , Asthma/immunology , Mice, Inbred C57BL , Mice , Cell Proliferation , Histocompatibility Antigens Class II/immunology , Histocompatibility Antigens Class II/metabolism , Antigens/immunology , Transforming Growth Factor beta/metabolism , Transforming Growth Factor beta/immunology , Interleukin-10/metabolism , Interleukin-10/immunology , Macrophages/immunology , Macrophages/metabolism , Lymphocyte Activation/immunology , Macrophages, Alveolar/immunology , Macrophages, Alveolar/metabolism , Mice, Inbred BALB CABSTRACT
The discovery of FOXP3+ regulatory T (Treg) cells as a distinct cell lineage with a central role in regulating immune responses provided a deeper understanding of self-tolerance. The transcription factor FOXP3 serves a key role in Treg cell lineage determination and maintenance, but is not sufficient to enable the full potential of Treg cell suppression, indicating that other factors orchestrate the fine-tuning of Treg cell function. Moreover, FOXP3-independent mechanisms have recently been shown to contribute to Treg cell dysfunction. FOXP3 mutations in humans cause lethal fulminant systemic autoinflammation (IPEX syndrome). However, it remains unclear to what degree Treg cell dysfunction is contributing to the pathophysiology of common autoimmune diseases. In this Review, we discuss the origins of Treg cells in the periphery and the multilayered mechanisms by which Treg cells are induced, as well as the FOXP3-dependent and FOXP3-independent cellular programmes that maintain the suppressive function of Treg cells in humans and mice. Further, we examine evidence for Treg cell dysfunction in the context of common autoimmune diseases such as multiple sclerosis, inflammatory bowel disease, systemic lupus erythematosus and rheumatoid arthritis.
Subject(s)
Autoimmune Diseases , Cell Differentiation , Forkhead Transcription Factors , T-Lymphocytes, Regulatory , T-Lymphocytes, Regulatory/immunology , Humans , Animals , Autoimmune Diseases/immunology , Forkhead Transcription Factors/immunology , Forkhead Transcription Factors/metabolism , Cell Differentiation/immunology , MiceABSTRACT
Pregnancy confers partner-specific protection against complications in future pregnancy that parallel persistence of fetal microchimeric cells (FMcs) in mothers after parturition. We show that preexisting FMcs become displaced by new FMcs during pregnancy and that FMc tonic stimulation is essential for expansion of protective fetal-specific forkhead box P3 (FOXP3)-positive regulatory T cells (Treg cells). Maternal microchimeric cells and accumulation of Treg cells with noninherited maternal antigen (NIMA) specificity are similarly overturned in daughters after pregnancy, highlighting a fixed microchimeric cell niche. Whereas NIMA-specific tolerance is functionally erased by pregnancy, partner-specific resiliency against pregnancy complications persists in mothers despite paternity changes in intervening pregnancy. Persistent fetal tolerance reflects FOXP3 expression plasticity, which allows mothers to more durably remember their babies, whereas daughters forget their mothers with new pregnancy-imprinted immunological memories.
Subject(s)
Chimerism , Fetus , Immune Tolerance , Immunologic Memory , Maternal-Fetal Exchange , Pregnancy , Animals , Female , Mice , Pregnancy/immunology , Antigens/immunology , Cell Plasticity , Fetus/cytology , Fetus/immunology , Forkhead Transcription Factors/immunology , Maternal-Fetal Exchange/immunology , Mice, Inbred C57BL , T-Lymphocytes, Regulatory/immunologyABSTRACT
Background: Asthma imposes a heavy burden due to its high prevalence. Forkhead box O4 (FoxO4) proteins participate in the modulation of cell progression. However, the role and mechanism of FoxO4 in asthma remains uncharted. Methods: An allergic asthma model was constructed by the induction of ovalbumin and interleukin (IL)-4 in mice and monocyte/macrophage-like Raw264.7 cells, respectively. The role and mechanism of FoxO4 in asthma was determined by pathological staining, immunofluorescence assay, measurement of inflammatory cells in the blood, reverse transcription quantitative polymerase chain reaction (RT-qPCR), Western blot analysis, and flow cytometry. Results: Ovalbumin treatment triggered an obvious inflammatory cell infiltration with a prominent increase in F4/80+ cell numbers. The relative messenger RNA (mRNA) and protein expressions of FoxO4 were increased in both ovalbumin-induced mice and interleukin-4 (IL-4)-induced Raw264.7 cells. Inhibition of FoxO4 via AS1842856 reduced inflammatory cell infiltration, the number of Periodic Acid Schiff+ (PAS+) goblet cells, the numbers of inflammatory cells in the blood, and the airway resistance in ovalbumin-induced mice. Besides, interference of FoxO4 decreased the number of F4/80+CD206+ cells, and the relative protein expressions of CD163 and Arg1 in vivo and in vitro. Mechanically, suppression of FoxO4 diminished the relative mRNA and protein expressions of LXA4R in both ovalbumin-induced mice and IL-4-induced Raw264.7 cells. Overexpression of LXA4R reversed the outcomes caused by repression of FoxO4, including airway resistance, the number of F4/80+ cells, the proportion of CD206+ cells in ovalbumin-induced mice, and the proportion of F4/80+CD206+ cells in IL-4-induced Raw264.7 cells. Conclusion: FoxO4/LXA4R axis mediated macrophage M2 polarization in allergic asthma (AU)
Subject(s)
Humans , Male , Mice , Asthma/immunology , Macrophages/immunology , Forkhead Transcription Factors/immunology , Disease Models, Animal , Animals, NewbornABSTRACT
Persistent immune activation, which occurs during the whole course of HIV infection, plays a pivotal role in CD4+ T cells depletion and AIDS progression. Furthermore, immune activation is a key factor that leads to impaired immune reconstitution after long-term effective antiretroviral therapy (ART), and is even responsible for the increased risk of developing non-AIDS co-morbidities. Therefore, it's imperative to identify an effective intervention targeting HIV-associated immune activation to improve disease management. Double negative T cells (DNT) were reported to provide immunosuppression during HIV infection, but the related mechanisms remained puzzled. Foxp3 endows Tregs with potent suppressive function to maintain immune homeostasis. However, whether DNT cells expressed Foxp3 and the accurate function of these cells urgently needed to be investigated. Here, we found that Foxp3+ DNT cells accumulated in untreated people living with HIV (PLWH) with CD4+ T cell count less than 200 cells/µl. Moreover, the frequency of Foxp3+ DNT cells was negatively correlated with CD4+ T cell count and CD4/CD8 ratio, and positively correlated with immune activation and systemic inflammation in PLWH. Of note, Foxp3+ DNT cells might exert suppressive regulation by increased expression of CD39, CD25, or vigorous proliferation (high levels of GITR and ki67) in ART-naive PLWH. Our study underlined the importance of Foxp3+ DNT cells in the HIV disease progression, and suggest that Foxp3+ DNT may be a potential target for clinical intervention for the control of immune activation during HIV infection.
Subject(s)
Forkhead Transcription Factors , HIV Infections , HIV-1 , T-Lymphocytes, Regulatory , Disease Progression , Forkhead Transcription Factors/immunology , HIV Infections/immunology , Humans , T-Lymphocytes, Regulatory/immunologyABSTRACT
Objective: To investigate the efficiency and potential mechanisms of exosomes from dendritic cells (DCs) transfected with Forkhead box protein P3 (FOXP3) in the development of experimental autoimmune encephalomyelitis (EAE). Method: Mouse bone marrow-derived immature DCs were loaded with adenovirus carrying FOXP3 gene, and exosomes were generated. Then the exosomes with FOXP3 (FOXP3-EXOs) were co-cultured with CD4+T cell in vitro to evaluate their potential on CD4+T cell proliferation and differentiation, and injected into EAE mice to assess their effects on the development of EAE. Result: FOXP3-EXOs were effective to inhibit the CD4+T cell proliferation and the production of Interferon gamma (IFN-γ), interleukin (IL)-6, and IL-17, while they promoted the production of IL-10 in vitro. Moreover, FOXP3-EXOs treatment significantly decreased the neurological scores, reduced the infiltration of inflammatory cells into the spinal cord, and decreased demyelination in comparison to saline and Con-EXOs treated EAE mice. Moreover, the FOXP3-EXOs treatment resulted in obvious increases in the levels of regulatory T (Treg) cells and IL-10, whereas levels of T helper 1 (Th1) cells, Th17 cells, IFN-γ, IL-6, and IL-17 decreased significantly in the splenocyte culture of EAE mice. Conclusion: The present study preliminarily investigated the effects and potential mechanisms of FOXP3-EXOs in EAE and revealed that the FOXP3-EXOs could inhibit the production of Th1 and Th17 cells and promote the production of Treg cells as well as ameliorate the development of EAE. The neuroprotective effects of FOXP3-EXOs on EAE are likely due to the regulation of Th/Treg balance.
Subject(s)
Dendritic Cells , Encephalomyelitis, Autoimmune, Experimental , Exosomes , Forkhead Transcription Factors , Animals , Dendritic Cells/immunology , Encephalomyelitis, Autoimmune, Experimental/genetics , Encephalomyelitis, Autoimmune, Experimental/immunology , Encephalomyelitis, Autoimmune, Experimental/therapy , Exosomes/genetics , Exosomes/immunology , Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/immunology , Interferon-gamma/immunology , Interleukin-10/genetics , Interleukin-10/immunology , Interleukin-17/immunology , Interleukin-6/genetics , Interleukin-6/immunology , Mice , Mice, Inbred C57BL , T-Lymphocyte Subsets/immunology , T-Lymphocytes, Regulatory , Th17 CellsABSTRACT
Persistence of hepatitis B virus (HBV) infection leading to chronic infection and its sequalae is responsible for over half a million deaths worldwide. The reason for persistence of chronic hepatitis B (CHB) infection is still not clearly understood. An attempt was made to understand the role of immune regulatory genes in CHB in comparison to spontaneously cleared HBV infection. Relative gene expression of 26 genes involved in innate immunity were studied using Real-Time Polymerase Chain Reaction Array. A total of 679 subjects from three different geographical regions of Northeast India (Assam, Arunachal Pradesh, and Tripura) were included in this case-control study. The cases were subdivided into CHB cases with HBeAg(+)(72), CHB with HBeAg(-)(278), spontaneously cleared controls (88), and healthy controls (228). Overall, 28.3% of the subjects had previous exposure with HBV, while 28.6% had protective antibodies IgG/IgM against HBV. There was a statistically higher number of CHB in men (66.4%) compared to women (33.6%) (p = 0.0001). Proto-oncogene FOS has been found to be moderately upregulated in CHB with HBeAg +ve (2.3-fold) and significantly upregulated (4.1-fold upregulation) in hepatocellular carcinoma. Further, FOXP3 was found to be significantly upregulated (3.0-fold, p = 0.01) in CHB with HBeAg (+) compared to spontaneously cleared HBV infection. In conclusion, CHB with HBeAg positivity was found to have disrupted immune response with upregulation of FOS and FOXP3. Thus, early induction of HBeAg seroconversion with interferon-based therapy or oral nucleos(t)ide analogs along with FOS inhibitors can have important clinical implications in the management of CHB and preventing cirrhosis and HCC.
Subject(s)
Forkhead Transcription Factors , Hepatitis B, Chronic , Antiviral Agents/therapeutic use , Case-Control Studies , Female , Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/immunology , Genes, Regulator , Hepatitis B e Antigens/immunology , Hepatitis B virus/immunology , Hepatitis B, Chronic/drug therapy , Hepatitis B, Chronic/genetics , Hepatitis B, Chronic/immunology , Humans , Immunity, Innate , Male , Proto-Oncogene Proteins c-fos/genetics , Proto-Oncogene Proteins c-fos/immunologyABSTRACT
Regulatory T (Treg) cells are critical in preventing aberrant immune responses. Posttranscriptional control of gene expression by microRNA (miRNA) has recently emerged as an essential genetic element for Treg cell function. Here, we report that mice with Treg cell-specific ablation of miR-142 (hereafter Foxp3CremiR-142fl/fl mice) developed a fatal systemic autoimmune disorder due to a breakdown in peripheral T-cell tolerance. Foxp3CremiR-142fl/fl mice displayed a significant decrease in the abundance and suppressive capacity of Treg cells. Expression profiling of miR-142-deficient Treg cells revealed an up-regulation of multiple genes in the interferon gamma (IFNγ) signaling network. We identified several of these IFNγ-associated genes as direct miR-142-3p targets and observed excessive IFNγ production and signaling in miR-142-deficient Treg cells. Ifng ablation rescued the Treg cell homeostatic defect and alleviated development of autoimmunity in Foxp3CremiR-142fl/fl mice. Thus, our findings implicate miR-142 as an indispensable regulator of Treg cell homeostasis that exerts its function by attenuating IFNγ responses.
Subject(s)
Autoimmunity/immunology , Gene Expression Regulation/immunology , Homeostasis/immunology , MicroRNAs/immunology , T-Lymphocytes, Regulatory/immunology , Acute Disease , Animals , Autoimmunity/genetics , Bone Marrow Transplantation/methods , Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/immunology , Forkhead Transcription Factors/metabolism , Gene Expression Profiling/methods , Graft vs Host Disease/immunology , Homeostasis/genetics , Interferon-gamma/genetics , Interferon-gamma/immunology , Interferon-gamma/metabolism , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , MicroRNAs/genetics , RNA-Seq/methods , Signal Transduction/genetics , T-Lymphocytes, Regulatory/metabolismABSTRACT
PURPOSE: We sought to understand the clinical course and molecular phenotype of patients who showed disease progression after programmed cell death ligand 1 (PD-L1) inhibitor treatment but subsequently responded to PD-1 inhibitor treatment. We also explored the response to PD-1-axis targeted therapy of classical Hodgkin lymphoma (cHL) according to genetically driven PD-L1 and programmed cell death ligand 2 (PD-L2) expression. METHODS: Five patients in a phase II clinical trial of CS1001 (PD-L1 inhibitor) for relapsed or refractory (R/R) cHL were retrospectively reviewed. Formalin-fixed, paraffin-embedded whole tissues from the five patients were evaluated for 9p24.1 genetic alterations based on FISH and the expression of PD-L1, PD-L2, PD-1, major histocompatibility complex (MHC) class I-II, and the tumor microenvironment factorsCD163 and FOXP3 in the microenvironmental niche, as revealed by multiplex immunofluorescence. RESULTS: All five patients showed primary refractory disease during first-line treatment. Four patients received PD-1 inhibitor after dropping out of the clinical trial, and all demonstrated at least a partial response. The progression-free survival ranged from 7 to 28 months (median = 18 months), and 9p24.1 amplification was observed in all five patients at the PD-L1/PD-L2 locus. PD-L1 and PD-L2 were colocalized on Hodgkin Reed-Sternberg (HRS) cells in four of the five (80%) patients. There was differential expression of PD-L1 and PD-L2 in cells in the tumor microenvironment in cHL, especially in HRS cells, background cells and tumor-associated macrophages. CONCLUSIONS: PD-L1 monotherapy may not be sufficient to block the PD-1 pathway; PD-L2 was expressed in HRS and background cells in cHL. The immunologic function of the PD-L2 pathway in anti-tumor activity may be underestimated in R/R cHL. Further study is needed to elucidate the anti-tumor mechanism of PD-1 inhibitor and PD-L1 inhibitor treatment.
Subject(s)
B7-H1 Antigen/antagonists & inhibitors , Hodgkin Disease/drug therapy , Immune Checkpoint Inhibitors/therapeutic use , Programmed Cell Death 1 Ligand 2 Protein/antagonists & inhibitors , Adult , Antigens, CD/immunology , Antigens, Differentiation, Myelomonocytic/immunology , Clinical Trials, Phase II as Topic , Female , Forkhead Transcription Factors/immunology , Histocompatibility Antigens/immunology , Hodgkin Disease/immunology , Humans , Male , Middle Aged , Programmed Cell Death 1 Receptor/immunology , Progression-Free Survival , Receptors, Cell Surface/immunology , Recurrence , Retrospective Studies , Treatment Outcome , Tumor Microenvironment/immunologyABSTRACT
Gene expression programs are specified by higher-order chromatin structure and enhancer-promoter loops (EPLs). T regulatory cell (Treg) identity is dominantly specified by the transcription factor (TF) FoxP3, whose mechanism of action is unclear. We applied chromatin conformation capture with immunoprecipitation (HiChIP) in Treg and closely related conventional CD4+ T cells (Tconv). EPLs identified by H3K27Ac HiChIP showed a range of connection intensity, with some superconnected genes. TF-specific HiChIP showed that FoxP3 interacts with EPLs at a large number of genes, including some not differentially expressed in Treg versus Tconv, but enriched at the core Treg signature loci that it up-regulates. FoxP3 association correlated with heightened H3K27Ac looping, as ascertained by analysis of FoxP3-deficient Treg-like cells. There was marked asymmetry in the loci where FoxP3 associated at the enhancer- or the promoter-side of EPLs, with enrichment for different transcriptional cofactors. FoxP3 EPL intensity distinguished gene clusters identified by single-cell ATAC-seq as covarying between individual Tregs, supporting a direct transactivation model for FoxP3 in determining Treg identity.
Subject(s)
Forkhead Transcription Factors/immunology , Promoter Regions, Genetic/genetics , T-Lymphocytes, Regulatory/immunology , Animals , Forkhead Transcription Factors/genetics , Gene Expression Regulation/genetics , Mice , Mice, Inbred C57BL , Mice, TransgenicABSTRACT
It is well known that interferon (IFN)-α/-ß activates the JAK/STAT signaling pathway and suppresses viral replication through the induction of IFN stimulated genes (ISGs). Here, we report that knockout of HDAC3 from macrophages results in the decreased expression of STAT1 and STAT2, leading to defective antiviral immunity in cells and mice. Further studies show that HDAC3 interacts with a conserved transcription factor Forkhead Box K1 (FOXK1), co-localizes with FOXK1 at the promoter of STAT1 and STAT2, and is required for protecting FOXK1 from lysosomal system-mediated degradation. FOXK1-deficient macrophages also show low STAT1 and STAT2 expression with defective responses to viruses. Thus, our studies uncover the biological importance of HDAC3 in regulating the antiviral immunity of macrophages through interacting with FOXK1 to regulate the expression of STAT1 and STAT2.
Subject(s)
Gene Expression Regulation/immunology , Histone Deacetylases/immunology , Immunity, Innate/immunology , Macrophages/immunology , Virus Diseases/immunology , Animals , Forkhead Transcription Factors/immunology , Mice , STAT1 Transcription Factor/biosynthesis , STAT1 Transcription Factor/immunology , STAT2 Transcription Factor/biosynthesis , STAT2 Transcription Factor/immunology , Transcription, GeneticABSTRACT
BACKGROUND: Caveolin-1 (CAV1) in cancer-associated fibroblasts (CAFs) has pro- or anti-tumourigenic effect depending on the cancer type. However, its effect in intrahepatic carcinoma (ICC) remains unknown. Therefore, this study aimed to investigate the relationship between CAV1 in CAFs and tumour-infiltrating lymphocyte (TIL) numbers or PD-L1 levels in ICC patients. METHODS: Consecutive ICC patients (n = 158) were enrolled in this study. The levels of CAV1 in CAFs, CD8 + TILs, Foxp3+ TILs and PD-L1 in cancer cells were analysed using immunohistochemistry. Their association with the clinicopathological factors and prognosis were evaluated. The correlation between these factors was evaluated. RESULTS: CAV1 upregulation in CAFs was associated with a poor overall survival (OS) (P < 0.001) and recurrence-free survival (P = 0.008). Clinicopathological factors were associated with high CA19-9 levels (P < 0.001), advanced tumour stage (P = 0.046) and lymph node metastasis (P = 0.004). CAV1 level was positively correlated with Foxp3+ TIL numbers (P = 0.01). There were no significant correlations between CAV1 levels and CD8 + TIL numbers (P = 0.80) and PD-L1 levels (P = 0.97). An increased CD8 + TIL number and decreased Foxp3+ TIL number were associated with an increased OS. In multivariate analysis, positive CAV1 expression in CAFs (P = 0.013) and decreased CD8 + TIL numbers (P = 0.021) were independent poor prognostic factors. CONCLUSION: Cellular senescence, represented by CAV1 levels, may be a marker of CAFs and a prognostic indicator of ICC through Foxp3+ TIL regulation. CAV1 expression in CAFs can be a therapeutic target for ICC.
Subject(s)
B7-H1 Antigen/metabolism , Cancer-Associated Fibroblasts/pathology , Caveolin 1/metabolism , Cellular Senescence , Cholangiocarcinoma/pathology , Forkhead Transcription Factors/metabolism , Lymphocytes, Tumor-Infiltrating/immunology , Aged , B7-H1 Antigen/immunology , Bile Duct Neoplasms/immunology , Bile Duct Neoplasms/metabolism , Bile Duct Neoplasms/pathology , CD8-Positive T-Lymphocytes/immunology , Cancer-Associated Fibroblasts/metabolism , Cholangiocarcinoma/immunology , Cholangiocarcinoma/metabolism , Female , Forkhead Transcription Factors/immunology , Humans , Male , Prognosis , Survival RateABSTRACT
Regulatory T (Treg) cells are critical for the maintenance of immune homeostasis. Dysregulation of Treg cells has been implicated in the pathogenesis of autoimmunity and chronic inflammation, while aging is characterized by an accumulation of inflammatory markers in the peripheral blood, a phenomenon known as 'inflammaging'. The relationship between Treg cells and age-related diseases remains to be further studied. Increasing evidence revealed that Treg cells' dysfunction occurs in aged patients, suggesting that immune therapies targeting Treg cells may be a promising approach to treat diseases such as cancers and autoimmune diseases. Furthermore, drugs targeting Treg cells show encouraging results and contribute to CD8+ T-cell-mediated cytotoxic killing of tumor and infected cells. In general, a better understanding of Treg cell function may help us to develop new immune therapies against aging. In this review, we discuss potential therapeutic strategies to modify immune responses of relevance for aging to prevent and treat age-related diseases, as well as the challenges posed by the translation of novel immune therapies into clinical practice.
Subject(s)
Aging/immunology , Forkhead Transcription Factors/genetics , Immunity/immunology , T-Lymphocytes, Regulatory/immunology , Aging/pathology , Autoimmune Diseases/immunology , Autoimmune Diseases/therapy , CD8-Positive T-Lymphocytes/immunology , Forkhead Transcription Factors/immunology , Homeostasis/immunology , Humans , Immunity/genetics , Inflammation/immunology , Inflammation/therapy , Leukocytes, Mononuclear/immunology , Neoplasms/immunology , Neoplasms/therapyABSTRACT
Understanding maternal immune tolerance is crucial for the development of therapeutics for immunological pregnancy complications. Decidual regulatory T cells (Tregs) play a pivotal role in the maintenance of maternal immune tolerance. Using a murine allogeneic pregnancy model in the current study, we identified the up-regulation of gonadotropin-releasing hormone receptor (GnRHR) in decidual T cell subsets including CD4+ conventional T cells, CD8+ T cells, and CD4+Foxp3+ Tregs. Using a lentivirus-mediated GnRHR overexpression system and a GnRHR agonist, we found that GnRHR activation decreased the expression of Treg functional molecules such as IL10 (IL-10), IL-35 subunit EBI3 (Ebi3), IL2RA (CD25), TNFRSF18 (GITR), ICOS, and Treg master regulator FOXP3. The functional analysis indicated that GnRHR activation impairs the ability of Tregs to inhibit conventional T cell proliferation. We also revealed that GnRHR activation suppressed the mechanistic target of rapamycin (mTOR) signaling in GnRHR-overexpressing splenic Tregs (Wild type C57BL/6 J background) and decidual Tregs. MHY1485, a potent mTOR activator, effectively abolished the effect of the GnRHR agonist and promoted the immunosuppressive capability of Tregs. Furthermore, in an adoptive transfer model, Treg-specific GnRHR knockdown increased Foxp3 expression in decidual Tregs while decreasing the production of IFN-γ and IL-17 in decidual effector CD4+ T cells and reducing the production of IFN-γ in decidual effector CD8+ T cells. Taken together, the present study unveils a novel mechanism by which the immunosuppressive function of decidual Tregs is modulated, and deepens our understanding of maternal immune tolerance.
Subject(s)
Immune Tolerance , Pregnancy , Receptors, LHRH , T-Lymphocytes, Regulatory , TOR Serine-Threonine Kinases , Animals , CD8-Positive T-Lymphocytes/immunology , Female , Forkhead Transcription Factors/immunology , Immune Tolerance/immunology , Mice , Pregnancy/immunology , Receptors, LHRH/immunology , T-Lymphocytes, Regulatory/immunology , TOR Serine-Threonine Kinases/immunologyABSTRACT
Regulatory T (Treg) cells, which constitute about 5-10% of CD4+T cells expressing Foxp3 transcription factor and CD25(IL-2 receptor α chain), are key regulators in controlling immunological self-tolerance and various immune responses. However, how Treg cells control antigen-specific immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains unclear. In this study, we examined the effect of transient breakdown of the immunological tolerance induced by Treg-cell depletion on adaptive immune responses against administered SARS-CoV-2 antigen, spike protein 1 (S1). Notably, without the use of adjuvants, transient Treg-cell depletion in mice induced anti-S1 antibodies that neutralized authentic SARS-CoV-2, follicular helper T cell formation and S1-binding germinal center B cell responses, but prevented the onset of developing autoimmune diseases. To further clarify the mechanisms, we investigated maturation of dendritic cells (DCs), which is essential to initiate antigen-specific immunity. We found that the transient Treg-cell depletion resulted in maturation of both migratory and resident DCs in draining lymph nodes that captured S1-antigen. Moreover, we observed S1-specific CD4+ T cells and CD8+ T cells with interferon-γ production. Thus, captured S1 was successfully presented by DCs, including cross-presentation to CD8+ T cells. These data indicate that transient Treg-cell depletion in the absence of adjuvants induces maturation of antigen-presenting DCs and succeeds in generating antigen-specific humoral and cellular immunity against emerging SARS-CoV-2 antigens. Finally, we showed that SARS-CoV-2 antigen-specific immune responses induced by transient Treg-cell depletion in the absence of adjuvants were compatible with those induced with an effective adjuvant, polyriboinosinic:polyribocytidyl acid (poly IC) and that the combination of transient Treg-cell depletion with poly IC induced potent responses. These findings highlight the capacity for manipulating Treg cells to induce protective adaptive immunity to SARS-CoV-2 with activating antigen-presenting DCs, which may improve the efficacy of ongoing vaccine therapies and help enhance responses to emerging SARS-CoV-2 variants.
Subject(s)
Adaptive Immunity/immunology , Antigens, Viral/immunology , COVID-19/immunology , Forkhead Transcription Factors/immunology , SARS-CoV-2/immunology , Animals , Antigen Presentation/immunology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/virology , Chlorocebus aethiops , Dendritic Cells/immunology , Female , Germinal Center/immunology , Humans , Immune Tolerance , Mice , Mice, Inbred C57BL , Mice, Inbred MRL lpr , T-Lymphocytes, Regulatory/immunology , Vero CellsABSTRACT
FOXP3+ regulatory T (Treg) cells are a unique subset of CD4+ T cells that classically function as master regulators of immune homeostasis. Besides this canonical suppressive role, which is required to maintain self-tolerance, a growing body of literature has identified Treg cells as critical orchestrators of tissue protection during acute stress and as effector cells that drive repair following tissue injury. Despite substantial interest in these distinct roles, the field has struggled to disentangle Treg cell suppressive functions from those that promote tissue defense and repair. In this article, we will examine the literature in the context of specific physiologic settings, contrasting the suppressive function of Treg cells with their emerging roles in promoting tissue homeostasis and tissue repair. Further, we will discuss a new paradigm differentiating tissue defense from tissue repair-a paradigm needed to translate Treg cell-based therapies to the clinic.
Subject(s)
Acute Lung Injury/immunology , Homeostasis/immunology , Immune Tolerance , T-Lymphocytes, Regulatory/immunology , Acute Lung Injury/metabolism , Animals , Forkhead Transcription Factors/immunology , Forkhead Transcription Factors/metabolism , Humans , T-Lymphocytes, Regulatory/metabolismABSTRACT
Transcription factors (TFs) modulate genes involved in cell-type-specific proliferative and migratory properties, metabolic features, and effector functions. Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most important pathogen agents in the porcine industry; however, TFs have been poorly studied during the course of this disease. Therefore, we aimed to evaluate the expressions of the TFs T-bet, GATA3, FOXP3, and Eomesodermin (EOMES) in target organs (the lung, tracheobronchial lymph node, and thymus) and those of different effector cytokines (IFNG, TNFA, and IL10) and the Fas ligand (FASL) during the early phase of infection with PRRSV-1 strains of different virulence. Target organs from mock-, virulent Lena-, and low virulent 3249-infected animals humanely euthanized at 1, 3, 6, 8, and 13 days post-infection (dpi) were collected to analyze the PRRSV viral load, histopathological lesions, and relative quantification through reverse transcription quantitative PCR (RT-qPCR) of the TFs and cytokines. Animals belonging to both infected groups, but mainly those infected with the virulent Lena strain, showed upregulation of the TFs T-bet, EOMES, and FOXP3, together with an increase of the cytokine IFN-γ in target organs at the end of the study (approximately 2 weeks post-infection). These results are suggestive of a stronger polarization to Th1 cells and regulatory T cells (Tregs), but also CD4+ cytotoxic T lymphocytes (CTLs), effector CD8+ T cells, and γδT cells in virulent PRRSV-1-infected animals; however, their biological functionality should be the object of further studies.