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2.
Epigenetics Chromatin ; 15(1): 24, 2022 06 30.
Article in English | MEDLINE | ID: mdl-35773720

ABSTRACT

BACKGROUND: Genome-wide association studies (GWAS) have enabled the discovery of single nucleotide polymorphisms (SNPs) that are significantly associated with many autoimmune diseases including type 1 diabetes (T1D). However, many of the identified variants lie in non-coding regions, limiting the identification of mechanisms that contribute to autoimmune disease progression. To address this problem, we developed a variant filtering workflow called 3DFAACTS-SNP to link genetic variants to target genes in a cell-specific manner. Here, we use 3DFAACTS-SNP to identify candidate SNPs and target genes associated with the loss of immune tolerance in regulatory T cells (Treg) in T1D. RESULTS: Using 3DFAACTS-SNP, we identified from a list of 1228 previously fine-mapped variants, 36 SNPs with plausible Treg-specific mechanisms of action. The integration of cell type-specific chromosome conformation capture data in 3DFAACTS-SNP identified 266 regulatory regions and 47 candidate target genes that interact with these variant-containing regions in Treg cells. We further demonstrated the utility of the workflow by applying it to three other SNP autoimmune datasets, identifying 16 Treg-centric candidate variants and 60 interacting genes. Finally, we demonstrate the broad utility of 3DFAACTS-SNP for functional annotation of all known common (> 10% allele frequency) variants from the Genome Aggregation Database (gnomAD). We identified 9376 candidate variants and 4968 candidate target genes, generating a list of potential sites for future T1D or other autoimmune disease research. CONCLUSIONS: We demonstrate that it is possible to further prioritise variants that contribute to T1D based on regulatory function, and illustrate the power of using cell type-specific multi-omics datasets to determine disease mechanisms. Our workflow can be customised to any cell type for which the individual datasets for functional annotation have been generated, giving broad applicability and utility.


Subject(s)
Diabetes Mellitus, Type 1 , T-Lymphocytes, Regulatory , Diabetes Mellitus, Type 1/genetics , Epigenesis, Genetic , Genome-Wide Association Study , Humans , Polymorphism, Single Nucleotide , T-Lymphocytes, Regulatory/physiology
3.
FASEB J ; 36(4): e22230, 2022 04.
Article in English | MEDLINE | ID: mdl-35233835

ABSTRACT

Norisoboldine (NOR), an alkaloid isolated from Radix Lindera, was previously reported to promote the differentiation of regulatory T cells (Treg cells), an important subtype of lymphocytes capable of controlling autoimmune diseases. The present study was performed to explore the mechanism of NOR in the view of cellular metabolism. A global metabolomic analysis indicated that NOR preferentially altered the fatty acid oxidation (FAO) pathway and elevated the content of related metabolites during Treg cell differentiation. The detection of oxygen consumption rate (OCR) and mRNA expression of FAO-related enzymes demonstrated that NOR promoted FAO in the early stage of Treg cell differentiation. Consistently, pharmacological or genetic inhibition of FAO markedly diminished the induction of NOR on Treg cell differentiation. Furthermore, NOR was shown to elevate the level of acetyl-CoA derived from FAO and acetylation of lysine 27 on histone 3 (H3K27) at the Foxp3 promoter and CNS2 regions. A knockdown of CPT1, the rate-limiting enzyme of FAO, weakened the promotion of NOR on the development, acetyl-CoA level, and acetylation of H3K27 of Treg cells in vitro and in the mice with collagen-induced arthritis, and attenuated the anti-arthritic effect of NOR. These findings demonstrate that NOR induces the development of Treg cells through promoting FAO, therefore, facilitating gene transcription of Foxp3 via acetyl-CoA-mediated H3K27 acetylation modification, and FAO might serve as a novel target to induce Treg cell development.


Subject(s)
Alkaloids/pharmacology , Fatty Acids/metabolism , Forkhead Transcription Factors/metabolism , Histones/metabolism , T-Lymphocytes, Regulatory/drug effects , Acetylation , Animals , Cell Differentiation/drug effects , Female , Forkhead Transcription Factors/genetics , Male , Mice , Mice, Inbred C57BL , Mice, Inbred DBA , Oxidation-Reduction , Promoter Regions, Genetic , T-Lymphocytes, Regulatory/cytology , T-Lymphocytes, Regulatory/physiology
5.
Life Sci ; 294: 120392, 2022 Apr 01.
Article in English | MEDLINE | ID: mdl-35149115

ABSTRACT

The SARS coronavirus 2 (SARS CoV-2) causes Coronavirus Disease (COVID-19), is an emerging viral infection. SARS CoV-2 infects target cells by attaching to Angiotensin-Converting Enzyme (ACE2). SARS CoV-2 could cause cardiac damage in patients with severe COVID-19, as ACE2 is expressed in cardiac cells, including cardiomyocytes, pericytes, and fibroblasts, and coronavirus could directly infect these cells. Cardiovascular disorders are the most frequent comorbidity found in COVID-19 patients. Immune cells such as monocytes, macrophages, and T cells may produce inflammatory cytokines and chemokines that contribute to COVID-19 pathogenesis if their functions are uncontrolled. This causes a cytokine storm in COVID-19 patients, which has been associated with cardiac damage. Tregs are a subset of immune cells that regulate immune and inflammatory responses. Tregs suppress inflammation and improve cardiovascular function through a variety of mechanisms. This is an exciting research area to explore the cellular, molecular, and immunological mechanisms related to reducing risks of cardiovascular complications in severe COVID-19. This review evaluated whether Tregs can affect COVID-19-related cardiovascular complications, as well as the mechanisms through which Tregs act.


Subject(s)
COVID-19/immunology , Cardiovascular Diseases/immunology , Cardiovascular Diseases/prevention & control , SARS-CoV-2 , T-Lymphocytes, Regulatory/physiology , Adoptive Transfer , Animals , Cardiovascular Diseases/virology , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/prevention & control , Humans , Inflammation/immunology , T-Lymphocytes, Regulatory/immunology
6.
BMC Nephrol ; 23(1): 51, 2022 02 02.
Article in English | MEDLINE | ID: mdl-35109826

ABSTRACT

BACKGROUND: Acute T-cell mediated rejection (aTCMR) is still an issue in kidney transplantation, for it is associated with chronic rejection, graft loss, and overall worse outcomes. For these reasons, a standard non-invasive molecular tool to detect is desirable to offer a simpler monitoring of kidney transplant recipients (KTRs). The purpose of our study was to examine, in peripheral blood before and after transplantation, the expression patterns of regulatory T cell (Treg)-related genes: the forkhead box P3 (FOXP3) and the two CTLA-4 isoforms (full-length and soluble) to predict acute rejection onset, de novo donor-specific antibodies (DSA) development and renal dysfunction 1 year after transplantation. METHODS: We profiled by using a relative quantification analysis (qRT-PCR) circulating mRNA levels of these biomarkers in peripheral blood of 89 KTRs within the first post-transplant year (at baseline and 15, 60 and 365 days, and when possible at the acute rejection) and compared also the results with 24 healthy controls. RESULTS: The three mRNA levels drastically reduced 15 days after transplantation and gradually recovered at 1 year in comparison with baseline, with very low levels at the time of aTCMR for FOXP3 (RQ = 0.445, IQR = 0.086-1.264, p = 0.040), maybe for the pro-apoptotic role of FOXP3 during inflammation. A multivariate Cox regression analysis evidenced a significant relation between aTCMR onset and thymoglobuline induction (HR = 6.749 p = 0.041), everolimus use (HR = 7.017, p = 0.007) and an increased risk from the solCTLA-4 expression at 15 days, mainly considering recipients treated with Mycophelolic acid (HR = 13.94 p = 0.038, 95%CI:1.157-167.87). Besides, solCTLA-4 also predisposed to graft dysfunction (eGFR< 60 mL/min/1.73m2) at 1 year (AOR = 3.683, 95%CI = 1.145-11.845, p = 0.029). On the other hand, pre-transplant solCTLA-4 levels showed a protective association with de novo DSAs development (HR = 0.189, 95%CI = 0.078-0.459, p < 0.001). CONCLUSIONS: mRNA levels of Treg-associated genes, mainly for solCTLA-4, in peripheral blood could put forward as candidate non-invasive biomarkers of cellular and humoral alloreactivity in clinical transplantation and might help shape immunosuppression, tailor monitoring and achieve better long-term outcomes of kidney transplantation in the wake of "precision medicine".


Subject(s)
CTLA-4 Antigen/genetics , Forkhead Transcription Factors/genetics , Graft Rejection/genetics , Kidney Transplantation , Postoperative Complications/genetics , RNA, Messenger/blood , T-Lymphocytes, Regulatory/physiology , Adult , Biomarkers/blood , Female , Gene Expression , Humans , Longitudinal Studies , Male , Middle Aged , Predictive Value of Tests , Treatment Outcome
7.
Malar J ; 21(1): 32, 2022 Feb 02.
Article in English | MEDLINE | ID: mdl-35109868

ABSTRACT

BACKGROUND: Regulatory T cells are known to play a key role to counter balance the protective immune response and immune mediated pathology. However, the role of naturally occurring regulatory cells CD4+CD25+Foxp3+ in malaria infection during the disease pathogenesis is controversial. Beside this, ICOS molecule has been shown to be involved in the development and function of regulatory T cell enhance IL-10 production. Therefore, possible involvement of the ICOS dependent regulatory CD4+ICOS+Foxp3+ T cells in resistance/susceptibility during malaria parasite is explored in this study. METHODS: 5 × 105 red blood cells infected with non-lethal and lethal parasites were inoculated in female Balb/c mice by intra-peritoneal injection. Infected or uninfected mice were sacrificed at early (3rd day post infection) and later stage (10th day post infection) of infection. Harvested cells were analysed by using flow cytometer and serum cytokine by Bioplex assay. RESULTS: Thin blood films show that percentages of parasitaemia increases with disease progression in infections with the lethal malaria parasite and mice eventually die by day 14th post-infection. Whereas in case of non-lethal malaria parasite, parasitaemia goes down by 7th day post infection and gets cleared within 13th day. The number of CD4+ ICOS+ T cells increases in lethal infection with disease progression. Surprisingly, in non-lethal parasite, ICOS expression decreases after day 7th post infection as parasitaemia goes down. The frequency of CD4+ICOS+FoxP3+ Tregs was significantly higher in lethal parasitic infection as compared to the non-lethal parasite. The level of IL-12 cytokine was remarkably higher in non-lethal infection compared to the lethal infection. In contrast, the level of IL-10 cytokines was higher in lethal parasite infection compared to the non-lethal parasite. CONCLUSION: Taken together, these data suggest that lethal parasite induce immunosuppressive environment, protecting from host immune responses and help the parasite to survive whereas non-lethal parasite leads to low frequencies of Treg cells seldom impede immune response that allow the parasite to get self-resolved.


Subject(s)
Malaria/etiology , T-Lymphocytes, Regulatory/physiology , Animals , CD4 Antigens/physiology , Cytokines/analysis , Female , Flow Cytometry , Forkhead Transcription Factors/physiology , Humans , Inducible T-Cell Co-Stimulator Protein/physiology , Interleukin-10/analysis , Malaria/diagnosis , Malaria/immunology , Mice , Mice, Inbred BALB C , Parasitemia/diagnosis , Parasitemia/parasitology , Peptide Fragments/physiology , Plasmodium berghei , Plasmodium chabaudi , Plasmodium yoelii , Specific Pathogen-Free Organisms , Spleen/cytology
8.
Diabetes ; 71(2): 264-274, 2022 02 01.
Article in English | MEDLINE | ID: mdl-34737186

ABSTRACT

A disparate array of plasma/serum markers provides evidence for chronic inflammation in human prediabetes, a condition that is most closely replicated by standard mouse models of obesity and metaflammation. These remain largely nonactionable and contrast with our rich understanding of inflammation in human type 2 diabetes. New data show that inflammatory profiles produced by CD4+ T cells define human prediabetes as a unique inflammatory state. Regulatory T cells (Treg) control mitochondrial function and cytokine production by CD4+ effector T cells (Teff) in prediabetes and type 2 diabetes by supporting T helper (Th)17 or Th1 cytokine production, respectively. These data suggest that Treg control of Teff metabolism regulates inflammation differentially in prediabetes compared with type 2 diabetes. Queries of genes that impact mitochondrial function or pathways leading to transcription of lipid metabolism genes identified the fatty acid importer CD36 as highly expressed in Treg but not Teff from subjects with prediabetes. Pharmacological blockade of CD36 in Treg from subjects with prediabetes decreased Teff production of the Th17 cytokines that differentiate overall prediabetes inflammation. We conclude that Treg control CD4+ T cell cytokine profiles through mechanisms determined, at least in part, by host metabolic status. Furthermore, Treg CD36 uniquely promotes Th17 cytokine production by Teff in prediabetes.


Subject(s)
CD4-Positive T-Lymphocytes/metabolism , Inflammation/immunology , Prediabetic State/immunology , T-Lymphocytes, Regulatory/physiology , CD4-Positive T-Lymphocytes/pathology , Cells, Cultured , Cohort Studies , Cytokines/metabolism , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/immunology , Diabetes Mellitus, Type 2/metabolism , Humans , Inflammation/genetics , Inflammation/metabolism , Obesity/complications , Obesity/genetics , Obesity/immunology , Obesity/metabolism , Prediabetic State/metabolism , Th17 Cells/metabolism , Transcriptome/immunology
9.
Ann Rheum Dis ; 81(1): 124-131, 2022 01.
Article in English | MEDLINE | ID: mdl-34583923

ABSTRACT

OBJECTIVES: Giant cell arteritis (GCA) is the most common primary vasculitis, preferentially affecting the aorta and its large-calibre branches. An imbalance between proinflammatory CD4+ T helper cell subsets and regulatory T cells (Tregs) is thought to be involved in the pathogenesis of GCA and Treg dysfunction has been associated with active disease. Our work aims to explore the aetiology of Treg dysfunction and the way it is affected by remission-inducing immunomodulatory regimens. METHODS: A total of 41 GCA patients were classified into active disease (n=14) and disease in remission (n=27). GCA patients' and healthy blood donors' (HD) Tregs were sorted and subjected to transcriptome and phenotypic analysis. RESULTS: Transcriptome analysis revealed 27 genes, which were differentially regulated between GCA-derived and HD-derived Tregs. Among those, we identified transcription factors, glycolytic enzymes and IL-2 signalling mediators. We confirmed the downregulation of forkhead box P3 (FOXP3) and interferon regulatory factor 4 (IRF4) at protein level and identified the ineffective induction of glycoprotein A repetitions predominant (GARP) and CD25 as well as the reduced T cell receptor (TCR)-induced calcium influx as correlates of Treg dysfunction in GCA. Inhibition of glycolysis in HD-derived Tregs recapitulated most identified dysfunctions of GCA Tregs, suggesting the central pathogenic role of the downregulation of the glycolytic enzymes. Separate analysis of the subgroup of tocilizumab-treated patients identified the recovery of the TCR-induced calcium influx and the Treg suppressive function to associate with disease remission. CONCLUSIONS: Our findings suggest that low glycolysis and calcium signalling account for Treg dysfunction and inflammation in GCA.


Subject(s)
Forkhead Transcription Factors/genetics , Giant Cell Arteritis/drug therapy , Giant Cell Arteritis/genetics , Interferon Regulatory Factors/genetics , T-Lymphocytes, Regulatory/physiology , Aged , Antibodies, Monoclonal, Humanized/therapeutic use , Calcium/metabolism , Calcium Signaling/genetics , Case-Control Studies , Down-Regulation , Female , Gene Expression Profiling , Giant Cell Arteritis/immunology , Glycolysis/genetics , Humans , Immunomodulating Agents/therapeutic use , Interleukin-2 Receptor alpha Subunit/genetics , Male , Membrane Proteins/genetics , Middle Aged , Phenotype
10.
Hepatol Commun ; 6(2): 320-333, 2022 02.
Article in English | MEDLINE | ID: mdl-34532981

ABSTRACT

Nonalcoholic steatohepatitis (NASH) is induced by steatosis and metabolic inflammation. While involvement of the innate immune response has been shown, the role of the adaptive immune response in NASH remains controversial. Likewise, the role of regulatory T cells (Treg) in NASH remains unclear although initial clinical trials aim to target these regulatory responses. High-fat high-carbohydrate (HF-HC) diet feeding of NASH-resistant BALB/c mice as well as the corresponding recombination activating 1 (Rag)-deficient strain was used to induce NASH and to study the role of the adaptive immune response. HF-HC diet feeding induced strong activation of intrahepatic T cells in BALB/c mice, suggesting an antigen-driven effect. In contrast, the effects of the absence of the adaptive immune response was notable. NASH in BALB/c Rag1-/- mice was substantially worsened and accompanied by a sharp increase of M1-like macrophage numbers. Furthermore, we found an increase in intrahepatic Treg numbers in NASH, but either adoptive Treg transfer or anti-cluster of differentiation (CD)3 therapy unexpectedly increased steatosis and the alanine aminotransferase level without otherwise affecting NASH. Conclusion: Although intrahepatic T cells were activated and marginally clonally expanded in NASH, these effects were counterbalanced by increased Treg numbers. The ablation of adaptive immunity in murine NASH led to marked aggravation of NASH, suggesting that Tregs are not regulators of metabolic inflammation but rather enhance it.


Subject(s)
Non-alcoholic Fatty Liver Disease/immunology , T-Lymphocytes, Regulatory/physiology , Adaptive Immunity , Adoptive Transfer , Alanine Transaminase/blood , Animals , Aspartate Aminotransferases/blood , CD3 Complex/immunology , Diet, Carbohydrate Loading , Diet, High-Fat , Disease Models, Animal , Disease Progression , Immunologic Factors/therapeutic use , Inflammation/physiopathology , Mice, Inbred BALB C , Non-alcoholic Fatty Liver Disease/enzymology , Non-alcoholic Fatty Liver Disease/physiopathology
11.
J Cancer Res Clin Oncol ; 148(2): 377-386, 2022 Feb.
Article in English | MEDLINE | ID: mdl-34739585

ABSTRACT

PURPOSE: Forkhead Box Protein 3 (FoxP3) is known as a key mediator in the immunosuppressive function of regulatory T-cells (Tregs). The aim of our study was to investigate whether FoxP3-positive Tregs have the potential to act as an independent predictor in progression as well as in regression of cervical intraepithelial neoplasia, especially in patients with intermediate cervical intraepithelial neoplasia (CIN II). METHODS: Nuclear FoxP3 expression was immunohistochemically analysed in 169 patient samples (CIN I, CIN II with regressive course, CIN II with progressive course, CIN III). The median numbers were calculated for each slide and correlated with the histological CIN grade. Statistical analysis was performed by SPSS 26 (Mann-Whitney U test, Spearman's rank correlation). RESULTS: An increased FoxP3 expression in CIN II with progression could be detected in comparison to CIN II with regression (p = 0.003). Total FoxP3 expression (epithelium and dysplasia-connected stroma) was higher in more advanced CIN grades (p < 0.001 for CIN I vs. CIN II; p = 0.227 for CIN II vs. CIN III). A positive correlation could be detected between FoxP3-positive cells in epithelium and total FoxP3 expression (Spearman's Rho: 0,565; p < 0.01). CONCLUSION: Expression of FoxP3 could be a helpful predictive factor to assess the risks of CIN II progression. As a prognosticator for regression and progression in cervical intraepithelial lesions it might thereby help in the decision process regarding surgical treatment vs. watchful waiting strategy to prevent conisation-associated risks for patients in child-bearing age. In addition, the findings support the potential of Tregs as a target for immune therapy in cervical cancer patients.


Subject(s)
Forkhead Transcription Factors/metabolism , T-Lymphocytes, Regulatory/physiology , Uterine Cervical Dysplasia/pathology , Uterine Cervical Neoplasms/pathology , Adolescent , Adult , Biomarkers, Tumor/metabolism , Disease Progression , Female , Germany , Humans , Immunohistochemistry , Middle Aged , Neoplasm Regression, Spontaneous/pathology , Papillomavirus Infections/immunology , Papillomavirus Infections/metabolism , Papillomavirus Infections/pathology , Prognosis , T-Lymphocytes, Regulatory/metabolism , T-Lymphocytes, Regulatory/pathology , Uterine Cervical Neoplasms/diagnosis , Uterine Cervical Neoplasms/immunology , Uterine Cervical Neoplasms/metabolism , Young Adult , Uterine Cervical Dysplasia/diagnosis , Uterine Cervical Dysplasia/immunology , Uterine Cervical Dysplasia/metabolism
12.
Shock ; 57(2): 230-237, 2022 02 01.
Article in English | MEDLINE | ID: mdl-34482318

ABSTRACT

ABSTRACT: Traumatic injuries, such as burn, are often complicated by ethanol intoxication at the time of injury. This leads to a myriad of complications and post-burn pathologies exacerbated by aberrant immune responses. Recent findings suggest that immune cell dysfunction in the gastrointestinal system is particularly important in deleterious outcomes associated with burn injuries. In particular, intoxication at the time of burn injury leads to compromised intestinal T cell responses, which can diminish intestinal immunity and promote bacterial translocation, allowing for increased secondary infections in the injured host and associated sequelae, such as multiple organ failure and sepsis. Regulatory T cells (Treg) have been identified as important mediators of suppressing effector T cell function. Therefore, the goal of this study was to assess the effects of ethanol intoxication and burn injury on Treg populations in small intestinal immune organs. We also evaluated the suppressive capability of Tregs isolated from injured animals. Male C57BL/6 mice were gavaged with 2.9 g/kg ethanol before receiving a ∼12.5% total body surface area scald burn. One day after injury, we identified a significant increase in Tregs number in small intestine Peyer's patches (∼×1.5) and lamina propria (∼×2). Tregs-producing cytokine IL-10 were also increased in both tissues. Finally, Tregs isolated from ethanol and burn-injured mice were able to suppress proliferation of effector T cells to a greater degree than sham vehicle Tregs. This was accompanied by increased levels of IL-10 and decreased levels of pro-proliferative cytokine IL-2 in cultures containing ethanol + burn Tregs compared with sham Tregs. These findings suggest that Treg populations are increased in intestinal tissues 1 day following ethanol intoxication and burn injury. Tregs isolated from ethanol and burn-injured animals also exhibit a greater suppression of effector T cell proliferation, which may contribute to altered T cell responses following injury.


Subject(s)
Alcoholic Intoxication/immunology , Burns/immunology , Intestine, Small/immunology , T-Lymphocytes, Regulatory/physiology , Animals , Male , Mice , Mice, Inbred C57BL
13.
Clin Transl Med ; 11(12): e625, 2021 12.
Article in English | MEDLINE | ID: mdl-34919342

ABSTRACT

Regulatory T cells (Tregs) play an important role in controlling autoimmunity and limiting tissue damage and inflammation. IL2-inducible T cell kinase (Itk) is part of the Tec family of tyrosine kinases and is a critical component of T cell receptor mediated signaling. Here, we showed that either genetic ablation of Itk signaling or inhibition of Itk signaling pathways resulted in increased frequency of "noncanonical" CD4+ CD25- FOXP3+ Tregs (ncTregs), as well as of "canonical" CD4+ CD25+ FOXP3+ Tregs (canTregs). Using in vivo models, we showed that ncTregs can avert the formation of acute graft-versus-host disease (GVHD), in part by reducing conventional T cell proliferation, proinflammatory cytokine production, and tissue damage. This reduction in GVHD occurred without disruption of graft-versus-leukaemia (GVL) effects. RNA sequencing revealed that a number of effector, cell adhesion, and migration molecules were upregulated in Itk-/- ncTregs. Furthermore, disrupting the SLP76: ITK interaction using a specific peptide inhibitor led to enhanced Treg development in both mouse and primary human cells. This peptide inhibitor also significantly reduced inflammatory cytokine production in primary GVHD patient samples and mouse T cells without causing cell death or apoptosis. We provide evidence that specifically targeting Itk signaling could be a therapeutic strategy to treat autoimmune disorders.


Subject(s)
Interleukin-2/pharmacology , T-Lymphocytes, Regulatory/drug effects , Animals , Disease Models, Animal , Enzyme-Linked Immunosorbent Assay/methods , Enzyme-Linked Immunosorbent Assay/statistics & numerical data , Erythrocytes/metabolism , Interleukin-2/metabolism , Mice , Mice, Inbred C57BL/genetics , Mice, Inbred C57BL/metabolism , Signal Transduction/drug effects , T-Lymphocytes, Regulatory/physiology
14.
Int J Mol Sci ; 22(20)2021 Oct 14.
Article in English | MEDLINE | ID: mdl-34681764

ABSTRACT

Vascularized composite allografts contain various tissue components and possess relative antigenicity, eliciting different degrees of alloimmune responses. To investigate the strategies for achieving facial allograft tolerance, we established a mouse hemiface transplant model, including the skin, muscle, mandible, mucosa, and vessels. However, the immunomodulatory effects of the mandible on facial allografts remain unclear. To understand the effects of the mandible on facial allograft survival, we compared the diversities of different facial allograft-elicited alloimmunity between a facial osteomyocutaneous allograft (OMC), including skin, muscle, oral mucosa, and vessels, and especially the mandible, and a myocutaneous allograft (MC) including the skin, muscle, oral mucosa, and vessels, but not the mandible. The different facial allografts of a BALB/c donor were transplanted into a heterotopic neck defect on fully major histocompatibility complex-mismatched C57BL/6 mice. The allogeneic OMC (Allo-OMC) group exhibited significant prolongation of facial allograft survival compared to the allogeneic MC group, both in the presence and absence of FK506 immunosuppressive drugs. With the use of FK506 monotherapy (2 mg/kg) for 21 days, the allo-OMC group, including the mandible, showed prolongation of facial allograft survival of up to 65 days, whereas the myocutaneous allograft, without the mandible, only survived for 34 days. The Allo-OMC group also displayed decreased lymphocyte infiltration into the facial allograft. Both groups showed similar percentages of B cells, T cells, natural killer cells, macrophages, and dendritic cells in the blood, spleen, and lymph nodes. However, a decrease in pro-inflammatory T helper 1 cells and an increase in anti-inflammatory regulatory T cells were observed in the blood and lymph nodes of the Allo-OMC group. Significantly increased percentages of donor immune cells were also observed in three lymphoid organs of the Allo-OMC group, suggesting mixed chimerism induction. These results indicated that the mandible has the potential to induce anti-inflammatory effects and mixed chimerism for prolonging facial allograft survival. The immunomodulatory understanding of the mandible could contribute to reducing the use of immunosuppressive regimens in clinical face allotransplantation including the mandible.


Subject(s)
Facial Transplantation/adverse effects , Graft Rejection/etiology , Mandible/physiology , T-Lymphocytes, Regulatory/physiology , Animals , Facial Transplantation/methods , Graft Rejection/immunology , Graft Survival/physiology , Immunosuppressive Agents/pharmacology , Mandible/immunology , Mandible/transplantation , Mice, Inbred BALB C , Mice, Inbred C57BL , Skin Transplantation/adverse effects , Skin Transplantation/methods , Tacrolimus/pharmacology , Transplantation Chimera/physiology , Transplantation, Homologous
15.
Elife ; 102021 10 15.
Article in English | MEDLINE | ID: mdl-34652270

ABSTRACT

Peripheral nerve injury-induced neuropathic pain is a chronic and debilitating condition characterized by mechanical hypersensitivity. We previously identified microglial activation via release of colony-stimulating factor 1 (CSF1) from injured sensory neurons as a mechanism contributing to nerve injury-induced pain. Here, we show that intrathecal administration of CSF1, even in the absence of injury, is sufficient to induce pain behavior, but only in male mice. Transcriptional profiling and morphologic analyses after intrathecal CSF1 showed robust immune activation in male but not female microglia. CSF1 also induced marked expansion of lymphocytes within the spinal cord meninges, with preferential expansion of regulatory T-cells (Tregs) in female mice. Consistent with the hypothesis that Tregs actively suppress microglial activation in females, Treg deficient (Foxp3DTR) female mice showed increased CSF1-induced microglial activation and pain hypersensitivity equivalent to males. We conclude that sexual dimorphism in the contribution of microglia to pain results from Treg-mediated suppression of microglial activation and pain hypersensitivity in female mice.


Subject(s)
Macrophage Colony-Stimulating Factor/genetics , Microglia/metabolism , Neuralgia/genetics , T-Lymphocytes, Regulatory/physiology , Animals , Female , Injections, Spinal , Macrophage Colony-Stimulating Factor/administration & dosage , Macrophage Colony-Stimulating Factor/metabolism , Male , Mice , Sex Factors
16.
Elife ; 102021 10 28.
Article in English | MEDLINE | ID: mdl-34709178

ABSTRACT

Cellular metabolism has key roles in T cells differentiation and function. CD4+ T helper-1 (Th1), Th2, and Th17 subsets are highly glycolytic while regulatory T cells (Tregs) use glucose during expansion but rely on fatty acid oxidation for function. Upon uptake, glucose can enter pentose phosphate pathway (PPP) or be used in glycolysis. Here, we showed that blocking 6-phosphogluconate dehydrogenase (6PGD) in the oxidative PPP resulted in substantial reduction of Tregs suppressive function and shifts toward Th1, Th2, and Th17 phenotypes which led to the development of fetal inflammatory disorder in mice model. These in turn improved anti-tumor responses and worsened the outcomes of colitis model. Metabolically, 6PGD blocked Tregs showed improved glycolysis and enhanced non-oxidative PPP to support nucleotide biosynthesis. These results uncover critical role of 6PGD in modulating Tregs plasticity and function, which qualifies it as a novel metabolic checkpoint for immunotherapy applications.


Subject(s)
Pentose Phosphate Pathway , Phosphogluconate Dehydrogenase/genetics , T-Lymphocytes, Regulatory/physiology , Animals , Mice , Phosphogluconate Dehydrogenase/metabolism
17.
Mediators Inflamm ; 2021: 2058964, 2021.
Article in English | MEDLINE | ID: mdl-34552387

ABSTRACT

Follicular helper CD4+ T (TFH) cells are a specialized subset of effector T cells that play a central role in orchestrating adaptive immunity. TFH cells mainly promote germinal center (GC) formation, provide help to B cells for immunoglobulin affinity maturation and class-switch recombination of B cells, and facilitate production of long-lived plasma cells and memory B cells. TFH cells express the nuclear transcriptional repressor B cell lymphoma 6 (Bcl-6), the chemokine (C-X-C motif) receptor 5 (CXCR5), the CD28 family members programmed cell death protein-1 (PD-1) and inducible costimulator (ICOS) and are also responsible for the secretion of interleukin-21 (IL-21) and IL-4. Follicular regulatory CD4+ T (TFR) cells, as a regulatory counterpart of TFH cells, participate in the regulation of GC reactions. TFR cells not only express markers of TFH cells but also express markers of regulatory T (Treg) cells containing FOXP3, glucocorticoid-induced tumor necrosis factor receptor (GITR), cytotoxic T lymphocyte antigen 4 (CTLA-4), and IL-10, hence owing to the dual characteristic of TFH cells and Treg cells. ICOS, expressed on activated CD4+ effector T cells, participates in T cell activation, differentiation, and effector process. The expression of ICOS is highest on TFH and TFR cells, indicating it as a key regulator of humoral immunity. Multiple sclerosis (MS) is a severe autoimmune disease that affects the central nervous system and results in disability, mediated by autoreactive T cells with evolving evidence of a remarkable contribution from humoral responses. This review summarizes recent advances regarding TFH cells, TFR cells, and ICOS, as well as their functional characteristics in relation to MS.


Subject(s)
Encephalomyelitis, Autoimmune, Experimental/etiology , Inducible T-Cell Co-Stimulator Protein/physiology , Multiple Sclerosis/etiology , T Follicular Helper Cells/physiology , T-Lymphocytes, Regulatory/physiology , Animals , Cell Differentiation , Encephalomyelitis, Autoimmune, Experimental/immunology , Humans , Multiple Sclerosis/immunology , T Follicular Helper Cells/classification
18.
Cancer Sci ; 112(11): 4478-4489, 2021 Nov.
Article in English | MEDLINE | ID: mdl-34545658

ABSTRACT

IL-2 is a pleiotropic cytokine that regulates immune cell homeostasis. Its immunomodulatory function has been used clinically as an active immunotherapy agent for metastatic cancers. However, severe adverse effects, including the vascular leak syndrome and the preferential stimulation of anti-immunogenic Treg rather than effector T cells, have been obstacles. We newly designed a mutein IL-2, Mutakine-6 (MK-6), with reduced IL-2Rα-binding capability. MK-6 induced comparable cell growth potential toward IL-2Rßγ-positive T cells but was far less efficient in in vitro Treg proliferation and STAT5 activation. Unlike IL-2, in vivo administration of MK-6 produced minimal adverse effects. Using CT26 and B16F10-syngeneic tumor models, we found MK-6 was highly efficacious on tumor regression. Serum albumin conjugation to MK-6 prolonged in vivo half-life and accumulated in CT26 tumors, showing enhanced antitumor effect. Tumor-infiltrating leukocytes analysis revealed that albumin-fused MK-6 increased the ratio of effector CD8+ T cells to CD4+ Treg cells. These results demonstrated that MK-6 is an efficient immunomodulator potentially used for improved immunotherapy with decreased adverse effects and attenuated Treg stimulation.


Subject(s)
CD4-Positive T-Lymphocytes/drug effects , Cell Proliferation/drug effects , Immunologic Factors/pharmacology , Lymphocytes, Tumor-Infiltrating/drug effects , T-Lymphocytes, Regulatory/drug effects , Animals , CD4-Positive T-Lymphocytes/cytology , Cell Line, Tumor , Disease Models, Animal , Female , Half-Life , Immunity, Cellular , Interleukin Receptor Common gamma Subunit/metabolism , Interleukin-2/adverse effects , Interleukin-2/metabolism , Interleukin-2/therapeutic use , Interleukin-2 Receptor alpha Subunit/metabolism , Interleukin-2 Receptor beta Subunit/metabolism , Lymphocytes, Tumor-Infiltrating/cytology , Lymphocytes, Tumor-Infiltrating/physiology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Phosphorylation , STAT5 Transcription Factor/metabolism , Serum Albumin/metabolism , T-Lymphocytes, Regulatory/cytology , T-Lymphocytes, Regulatory/physiology , Tumor Suppressor Proteins/metabolism
19.
JCI Insight ; 6(18)2021 09 22.
Article in English | MEDLINE | ID: mdl-34403374

ABSTRACT

Oligoarticular juvenile idiopathic arthritis (oligo JIA) is the most common form of chronic inflammatory arthritis in children, yet the cause of this disease remains unknown. To understand immune responses in oligo JIA, we immunophenotyped synovial fluid T cells with flow cytometry, bulk RNA-Seq, single-cell RNA-Seq (scRNA-Seq), DNA methylation studies, and Treg suppression assays. In synovial fluid, CD4+, CD8+, and γδ T cells expressed Th1-related markers, whereas Th17 cells were not enriched. Th1 skewing was prominent in CD4+ T cells, including Tregs, and was associated with severe disease. Transcriptomic studies confirmed a Th1 signature in CD4+ T cells from synovial fluid. The regulatory gene expression signature was preserved in Tregs, even those exhibiting Th1 polarization. These Th1-like Tregs maintained Treg-specific methylation patterns and suppressive function, supporting the stability of this Treg population in the joint. Although synovial fluid CD4+ T cells displayed an overall Th1 phenotype, scRNA-Seq uncovered heterogeneous effector and regulatory subpopulations, including IFN-induced Tregs, peripheral helper T cells, and cytotoxic CD4+ T cells. In conclusion, oligo JIA is characterized by Th1 polarization that encompasses Tregs but does not compromise their regulatory identity. Targeting Th1-driven inflammation and augmenting Treg function may represent important therapeutic approaches in oligo JIA.


Subject(s)
Arthritis, Juvenile/immunology , Cell Polarity , Synovial Fluid/immunology , T-Lymphocytes/physiology , Adolescent , Arthritis, Juvenile/genetics , CD4-Positive T-Lymphocytes/physiology , CD8-Positive T-Lymphocytes/physiology , Case-Control Studies , Child , Child, Preschool , DNA Methylation , Female , Humans , Immunophenotyping , Infant , Intraepithelial Lymphocytes/physiology , Male , Sequence Analysis, RNA , Single-Cell Analysis , T-Lymphocytes, Regulatory/physiology , Th1 Cells/physiology , Transcriptome
20.
Proc Natl Acad Sci U S A ; 118(37)2021 09 14.
Article in English | MEDLINE | ID: mdl-34433692

ABSTRACT

The hallmark of severe COVID-19 is an uncontrolled inflammatory response, resulting from poorly understood immunological dysfunction. We hypothesized that perturbations in FoxP3+ T regulatory cells (Treg), key enforcers of immune homeostasis, contribute to COVID-19 pathology. Cytometric and transcriptomic profiling revealed a distinct Treg phenotype in severe COVID-19 patients, with an increase in Treg proportions and intracellular levels of the lineage-defining transcription factor FoxP3, correlating with poor outcomes. These Tregs showed a distinct transcriptional signature, with overexpression of several suppressive effectors, but also proinflammatory molecules like interleukin (IL)-32, and a striking similarity to tumor-infiltrating Tregs that suppress antitumor responses. Most marked during acute severe disease, these traits persisted somewhat in convalescent patients. A screen for candidate agents revealed that IL-6 and IL-18 may individually contribute different facets of these COVID-19-linked perturbations. These results suggest that Tregs may play nefarious roles in COVID-19, by suppressing antiviral T cell responses during the severe phase of the disease, and by a direct proinflammatory role.


Subject(s)
COVID-19/etiology , T-Lymphocytes, Regulatory/physiology , Adult , Aged , CD4-Positive T-Lymphocytes/virology , Female , Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/metabolism , Gene Expression Profiling , Gene Expression Regulation , Humans , Inflammation/metabolism , Inflammation/virology , Interleukin-18/genetics , Interleukin-18/metabolism , Interleukin-2 Receptor alpha Subunit/genetics , Interleukin-2 Receptor alpha Subunit/metabolism , Interleukin-6/genetics , Interleukin-6/metabolism , Lymphocytes, Tumor-Infiltrating/physiology , Male , Middle Aged , Severity of Illness Index , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/virology , Transcription Factors/genetics , Transcription Factors/metabolism
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