1 3893 87 LACTATE INDUCES METABOLIC AND EPIGENETIC REPROGRAMMING OF PRO-INFLAMMATORY TH17 CELLS. INCREASED LACTATE LEVELS IN THE TISSUE MICROENVIRONMENT ARE A WELL-KNOWN FEATURE OF CHRONIC INFLAMMATION. HOWEVER, THE ROLE OF LACTATE IN REGULATING T CELL FUNCTION REMAINS CONTROVERSIAL. HERE, WE DEMONSTRATE THAT EXTRACELLULAR LACTATE PREDOMINANTLY INDUCES DEREGULATION OF THE TH17-SPECIFIC GENE EXPRESSION PROGRAM BY MODULATING THE METABOLIC AND EPIGENETIC STATUS OF TH17 CELLS. FOLLOWING LACTATE TREATMENT, TH17 CELLS SIGNIFICANTLY REDUCED THEIR IL-17A PRODUCTION AND UPREGULATED FOXP3 EXPRESSION THROUGH ROS-DRIVEN IL-2 SECRETION. MOREOVER, WE OBSERVED INCREASED LEVELS OF GENOME-WIDE HISTONE H3K18 LACTYLATION, A RECENTLY DESCRIBED MARKER FOR ACTIVE CHROMATIN IN MACROPHAGES, IN LACTATE-TREATED TH17 CELLS. IN ADDITION, WE SHOW THAT HIGH LACTATE CONCENTRATIONS SUPPRESS TH17 PATHOGENICITY DURING INTESTINAL INFLAMMATION IN MICE. THESE RESULTS INDICATE THAT LACTATE IS CAPABLE OF REPROGRAMMING PRO-INFLAMMATORY T CELL PHENOTYPES INTO REGULATORY T CELLS. 2022 2 2389 26 EPIGENETIC REPOLARIZATION OF T LYMPHOCYTES FROM CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS USING 5-AZA-2'-DEOXYCYTIDINE. T CELL IMMUNE DYSFUNCTION HAS AN IMPORTANT ROLE IN THE PROFOUND IMMUNE SUPPRESSION THAT CHARACTERIZES CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). IMPROPER POLARIZATION OF T CELLS HAS BEEN PROPOSED AS ONE OF THE MECHANISM INVOLVED. MOUNTING DATA IMPLICATES CHROMATIN REGULATION, NAMELY PROMOTER METHYLATION, IN THE PLASTICITY OF NAIVE HUMAN T CELLS. RECENT IN VITRO EVIDENCE INDICATES THAT THIS PLASTICITY MAY BE PHENOTYPICALLY ALTERED BY USING METHYLATION INHIBITORS WHICH ARE APPROVED FOR CLINICAL USE IN CERTAIN TYPES OF CANCER. THESE RESULTS BEG THE QUESTION: CAN THE INEFFECTIVE POLARIZATION OF T LYMPHOCYTES IN THE CONTEXT OF CLL BE EFFECTIVELY MODULATED USING METHYLATION INHIBITORS IN A SUSTAINABLE THERAPEUTIC FASHION? TO ANSWER THIS QUESTION OUR LABORATORY HAS STUDIED THE EFFECTS OF 5-AZA-2'-DEOXYCYTIDINE (5A2) IN HELPER AND CYTOTOXIC T LYMPHOCYTES FROM HEALTHY DONORS AND CLL PATIENTS IN WELL CHARACTERIZED MOLECULAR AND EPIGENETIC SIGNALING PATHWAYS INVOLVED IN EFFECTIVE POLARIZATION. MOREOVER, WE SOUGHT TO INVESTIGATE THE CONSEQUENCES OF METHYLATION INHIBITOR TREATMENT ON LYMPHOCYTE SURVIVAL, ACTIVATION INTENSITY, AND NAIVE CELL POLARIZATION. OUR DATA INDICATES THAT 5A2 TREATMENT CAN DEPOLARIZE TH2 CELLS TO EFFECTIVELY SECRETE INTERFERON GAMMA, SIGNAL VIA T-BET, AND ACHIEVE DEMETHYLATION OF CRITICAL TH1 SPECIFIC PROMOTERS. MOREOVER, WE DEMONSTRATE THAT 5A2 CAN FORCE TH1 POLARIZATION OF NAIVE T CELLS DESPITE A STRONG IL-4 STIMULI AND A LACK OF IL-12. IN CONCLUSION OUR DATA SEEKS TO DEFINE A MODALITY IN WHICH IMPROPER OR INEFFECTIVE T CELL POLARIZATION CAN BE ALTERED BY 5AZA AND COULD BE INCORPORATED IN FUTURE THERAPEUTIC INTERVENTIONS. 2011 3 6057 20 THE DARK SIDE OF REGULATORY T CELLS IN PSORIASIS. PSORIASIS IS A HEREDITARY DISEASE ELICITED BY CHRONIC ACTIVATION OF CUTANEOUS T CELLS. DELINEATING THE MECHANISTIC INTERPLAY OF THE CELL SUBSETS INVOLVED IS KEY TO DEVELOPING THE NEXT GENERATION OF EFFECTIVE TREATMENTS. IN THIS ISSUE, BOVENSCHEN ET AL. REPORT THAT REGULATORY T CELLS MAINTAIN A FINE BALANCE BETWEEN THE TRANSCRIPTION FACTORS FOXP3 AND RORGAMMAT. IN PATIENTS WITH PSORIASIS, TREGS READILY TURN INTO IL-17-EXPRESSING CELLS, THUS POTENTIALLY PERPETUATING THE INFLAMMATORY PROCESS THAT CHARACTERIZES THE DISEASE. RESULTS DEMONSTRATING THAT THE HISTONE/PROTEIN DEACETYLATION INHIBITOR TRICHOSTATIN A CAN BLOCK THIS CONVERSION SUGGEST THAT AN EPIGENETIC MODIFICATION MAY UNDERLIE REGULATORY T-CELL PLASTICITY. 2011 4 3527 24 IL-6 ENHANCES THE NUCLEAR TRANSLOCATION OF DNA CYTOSINE-5-METHYLTRANSFERASE 1 (DNMT1) VIA PHOSPHORYLATION OF THE NUCLEAR LOCALIZATION SEQUENCE BY THE AKT KINASE. THE EPIGENETIC PROGRAMMING OF GENOMIC DNA IS ACCOMPLISHED, IN PART, BY SEVERAL DNA CYTOSINE-5-METHYLTRANSFERASES THAT ACT BY COVALENTLY MODIFYING CYTOSINES WITH THE ADDITION OF A METHYL GROUP. THIS COVALENT MODIFICATION IS MAINTAINED BY THE DNA CYTOSINE-5-METHYLTRANSFERASE-1 ENZYME (DNMT1), WHICH IS CAPABLE OF ACTING IN CONCERT WITH OTHER SIMILAR ENZYMES TO SILENCE IMPORTANT TUMOR SUPPRESSOR GENES. IL-6 IS A MULTIFUNCTIONAL MEDIATOR OF INFLAMMATION, ACTING THROUGH SEVERAL MAJOR SIGNALING CASCADES, INCLUDING THE PHOSPHATIDYLINOSITOL-3-KINASE PATHWAY (PI-3-K), WHICH ACTIVATES PROTEIN KINASE B (AKT/PKB) DOWNSTREAM. HERE, WE SHOW THAT THE SUBCELLULAR LOCALIZATION OF DNMT1 CAN BE ALTERED BY THE ADDITION OF IL-6, INCREASING THE RATE OF NUCLEAR TRANSLOCATION OF THE ENZYME FROM THE CYTOSOLIC COMPARTMENT. THE MECHANISM OF NUCLEAR TRANSLOCATION OF DNMT1 IS GREATLY ENHANCED BY PHOSPHORYLATION OF THE DNMT1 NUCLEAR LOCALIZATION SIGNAL (NLS) BY PKB/AKT KINASE. MUTAGENIC ALTERATION OF THE TWO AKT TARGET AMINO ACIDS WITHIN THE NLS RESULTS IN A MAJOR LOSS OF DNMT1 NUCLEAR TRANSLOCATION, WHILE THE CREATION OF A "PHOSPHO-MIMIC" AMINO ACID (MUTATION TO ACIDIC RESIDUES) RESTORES THIS COMPARTMENTATION ABILITY. THESE OBSERVATIONS SUGGEST AN INTERESTING HYPOTHESIS REGARDING HOW MEDIATORS OF CHRONIC INFLAMMATION MAY DISTURB THE DELICATE BALANCE OF CELLULAR COMPARTMENTALIZATION OF IMPORTANT PROTEINS, AND REVEALS A POTENTIAL MECHANISM FOR THE INDUCTION OR ENHANCEMENT OF TUMOR GROWTH VIA ALTERATION OF THE COMPONENTS INVOLVED IN THE EPIGENETIC PROGRAMMING OF A CELL. 2007 5 6765 33 ZINC DEFICIENCY LEADS TO REDUCED INTERLEUKIN-2 PRODUCTION BY ACTIVE GENE SILENCING DUE TO ENHANCED CREMALPHA EXPRESSION IN T CELLS. BACKGROUND & AIMS: THE MICRONUTRIENT ZINC IS ESSENTIAL FOR PROPER IMMUNE FUNCTION. CONSEQUENTLY, ZINC DEFICIENCY LEADS TO IMPAIRED IMMUNE FUNCTION, AS SEEN IN DECREASED SECRETION OF INTERLEUKIN (IL)-2 BY T CELLS. ALTHOUGH THIS ASSOCIATION HAS BEEN KNOWN SINCE THE LATE 1980S, THE UNDERLYING MOLECULAR MECHANISMS ARE STILL UNKNOWN. ZINC DEFICIENCY AND REDUCED IL-2 LEVELS ARE ESPECIALLY FOUND IN THE ELDERLY, WHICH IN TURN ARE PRONE TO CHRONIC DISEASES. HERE, WE DESCRIBE A NEW MOLECULAR LINK BETWEEN ZINC DEFICIENCY AND REDUCED IL-2 EXPRESSION IN T CELLS. METHODS: THE EFFECTS OF ZINC DEFICIENCY WERE FIRST INVESTIGATED IN VITRO IN THE HUMAN T CELL LINES JURKAT AND HUT-78 AND COMPLEMENTED BY IN VIVO DATA FROM ZINC-SUPPLEMENTED PIGS. A SHORT- AND LONG-TERM MODEL FOR ZINC DEFICIENCY WAS ESTABLISHED. ZINC LEVELS WERE DETECTED BY FLOW CYTOMETRY AND EXPRESSION PROFILES WERE INVESTIGATED ON THE MRNA AND PROTEIN LEVEL. RESULTS: THE EXPRESSION OF THE TRANSCRIPTION FACTOR CAMP-RESPONSIVE-ELEMENT MODULATOR ALPHA (CREMALPHA) IS INCREASED DURING ZINC DEFICIENCY IN VITRO, DUE TO INCREASED PROTEIN PHOSPHATASE 2A (PP2A) ACTIVITY, RESULTING IN DECREASED IL-2 PRODUCTION. ADDITIONALLY, ZINC SUPPLEMENTATION IN VIVO REDUCED CREMALPHA LEVELS CAUSING INCREASED IL-2 EXPRESSION. ON EPIGENETIC LEVELS INCREASED CREMALPHA BINDING TO THE IL-2 PROMOTER IS MEDIATED BY HISTONE DEACETYLASE 1 (HDAC1). THE HDAC1 ACTIVITY IS INHIBITED BY ZINC. MOREOVER, DEACETYLATION OF THE ACTIVATING HISTONE MARK H3K9 WAS INCREASED UNDER ZINC DEFICIENCY, RESULTING IN REDUCED IL-2 EXPRESSION. CONCLUSIONS: WITH THE TRANSCRIPTION FACTOR CREMALPHA A MOLECULAR LINK WAS UNCOVERED, CONNECTING ZINC DEFICIENCY WITH REDUCED IL-2 PRODUCTION DUE TO ENHANCED PP2A AND HDAC1 ACTIVITY. 2021 6 5872 20 SUSTAINED TNF-ALPHA STIMULATION LEADS TO TRANSCRIPTIONAL MEMORY THAT GREATLY ENHANCES SIGNAL SENSITIVITY AND ROBUSTNESS. TRANSCRIPTIONAL MEMORY ALLOWS CERTAIN GENES TO RESPOND TO PREVIOUSLY EXPERIENCED SIGNALS MORE ROBUSTLY. HOWEVER, WHETHER AND HOW THE KEY PROINFLAMMATORY CYTOKINE TNF-ALPHA MEDIATES TRANSCRIPTIONAL MEMORY ARE POORLY UNDERSTOOD. USING HEK293F CELLS AS A MODEL SYSTEM, WE REPORT THAT SUSTAINED TNF-ALPHA STIMULATION INDUCES TRANSCRIPTIONAL MEMORY DEPENDENT ON TET ENZYMES. THE HYPOMETHYLATED STATUS OF TRANSCRIPTIONAL REGULATORY REGIONS CAN BE INHERITED, FACILITATING NF-KAPPAB BINDING AND MORE ROBUST SUBSEQUENT ACTIVATION. A HIGH INITIAL METHYLATION LEVEL AND CPG DENSITY AROUND KAPPAB SITES ARE CORRELATED WITH THE FUNCTIONAL POTENTIAL OF TRANSCRIPTIONAL MEMORY MODULES. INTERESTINGLY, THE CALCB GENE, ENCODING THE PROVEN MIGRAINE THERAPEUTIC TARGET CGRP, EXHIBITS THE BEST TRANSCRIPTIONAL MEMORY. A NEIGHBORING PRIMATE-SPECIFIC ENDOGENOUS RETROVIRUS STIMULATES MORE RAPID, MORE STRONG, AND AT LEAST 100-FOLD MORE SENSITIVE CALCB INDUCTION IN SUBSEQUENT TNF-ALPHA STIMULATION. OUR STUDY REVEALS THAT TNF-ALPHA-MEDIATED TRANSCRIPTIONAL MEMORY IS GOVERNED BY ACTIVE DNA DEMETHYLATION AND GREATLY SENSITIZES MEMORY GENES TO MUCH LOWER DOSES OF INFLAMMATORY CUES. 2020 7 1618 27 DNA METHYLTRANSFERASE INHIBITORS INCREASE NOD-LIKE RECEPTOR ACTIVITY AND EXPRESSION IN A MONOCYTIC CELL LINE. BACKGROUND: THE INTRACELLULAR NOD-LIKE RECEPTOR (NLR) FAMILY OF PATHOGEN RECOGNITION RECEPTORS (PRRA) IS INVOLVED IN INITIATING THE INNATE IMMUNE RESPONSE OF WHICH NOD1 AND NOD2 ARE THE BEST-CHARACTERIZED MEMBERS. ABERRANT EXPRESSION OF NOD1 AND NOD2 HAS BEEN UNCOVERED IN A NUMBER OF CHRONIC INFLAMMATORY DISEASES, SUCH AS INFLAMMATORY BOWEL DISEASE AND RHEUMATOID ARTHRITIS. HOWEVER, THE MECHANISM UNDERLYING NOD1/NOD2 GENE EXPRESSION REGULATION IS STILL IN ITS INFANCY. EPIGENETIC MODIFICATIONS SUCH AS DNA METHYLATION AND HISTONE ACETYLATION REGULATE THE EXPRESSION OF GENES AND ALTERATIONS IN THEIR PATTERNS HAVE BEEN LINKED TO MANY INFLAMMATORY DISEASES. THIS STUDY INVESTIGATED WHETHER EPIGENETIC MODIFYING DRUGS AFFECT THE REGULATION OF NOD1/NOD2 ACTIVITY AND EXPRESSION. DNA METHYLTRANSFERASE INHIBITORS HAVE RECENTLY BEEN USED IN THE TREATMENT OF MYELODYSPLASTIC SYNDROME AND AS COMBINATION THERAPY IN CANCER BUT THE FULL EXTENT OF THEIR EFFECTS HAS NOT BEEN QUANTIFIED.METHODS: PHARMACOLOGICAL INHIBITION OF EPIGENETIC ENZYMES IN A HUMAN MONOCYTIC THP-1 CELL LINE WAS CARRIED OUT AND NOD1/NOD2 EXPRESSION AND PRO-INFLAMMATORY RESPONSES WERE QUANTIFIED.RESULTS: CELLS PRIMED WITH A DNA METHYLTRANSFERASE INHIBITOR (BUT NOT A HISTONE DEACETYLASE [HDAC] INHIBITOR) WERE FOUND TO BE CONSISTENTLY MORE RESPONSIVE TO NOD1/NOD2 STIMULATION AND HAD INCREASED BASAL EXPRESSION.CONCLUSION: THE NOVEL EXPERIMENTATION CARRIED OUT HERE SUGGESTS FOR THE FIRST TIME THAT NOD1/NOD2 RECEPTOR ACTIVITY AND EXPRESSION IN MONOCYTES ARE POSSIBLY REGULATED DIRECTLY BY DNA METHYLATION. 2022 8 2926 25 GENERATION OF AN EPIGENETIC SIGNATURE BY CHRONIC HYPOXIA IN PROSTATE CELLS. INCREASING LEVELS OF TISSUE HYPOXIA HAVE BEEN REPORTED AS A NATURAL FEATURE OF THE AGING PROSTATE GLAND AND MAY BE A RISK FACTOR FOR THE DEVELOPMENT OF PROSTATE CANCER. IN THIS STUDY, WE HAVE USED PWR-1E BENIGN PROSTATE EPITHELIAL CELLS AND AN EQUIVALENTLY AGED HYPOXIA-ADAPTED PWR-1E SUB-LINE TO IDENTIFY PHENOTYPIC AND EPIGENETIC CONSEQUENCES OF CHRONIC HYPOXIA IN PROSTATE CELLS. WE HAVE IDENTIFIED A SIGNIFICANTLY ALTERED CELLULAR PHENOTYPE IN RESPONSE TO CHRONIC HYPOXIA AS CHARACTERIZED BY INCREASED RECEPTOR-MEDIATED APOPTOTIC RESISTANCE, THE INDUCTION OF CELLULAR SENESCENCE, INCREASED INVASION AND THE INCREASED SECRETION OF IL-1 BETA, IL6, IL8 AND TNFALPHA CYTOKINES. IN ASSOCIATION WITH THESE PHENOTYPIC CHANGES AND THE ABSENCE OF HIF-1 ALPHA PROTEIN EXPRESSION, WE HAVE DEMONSTRATED SIGNIFICANT INCREASES IN GLOBAL LEVELS OF DNA METHYLATION AND H3K9 HISTONE ACETYLATION IN THESE CELLS, CONCOMITANT WITH THE INCREASED EXPRESSION OF DNA METHYLTRANSFERASE DMNT3B AND GENE-SPECIFIC CHANGES IN DNA METHYLATION AT KEY IMPRINTING LOCI. IN CONCLUSION, WE HAVE DEMONSTRATED A GENOME-WIDE ADJUSTMENT OF DNA METHYLATION AND HISTONE ACETYLATION UNDER CHRONIC HYPOXIC CONDITIONS IN THE PROSTATE. THESE EPIGENETIC SIGNATURES MAY REPRESENT AN ADDITIONAL MECHANISM TO PROMOTE AND MAINTAIN A HYPOXIC-ADAPTED CELLULAR PHENOTYPE WITH A POTENTIAL ROLE IN TUMOUR DEVELOPMENT. 2009 9 2146 26 EPIGENETIC MANIPULATION RESTORES FUNCTIONS OF DEFECTIVE CD8(+) T CELLS FROM CHRONIC VIRAL INFECTION. FUNCTIONAL EXHAUSTION OF ANTIGEN-SPECIFIC T CELLS IS A DEFINING CHARACTERISTIC OF MANY CHRONIC INFECTIONS, BUT THE UNDERLYING MECHANISMS OF T CELL DYSFUNCTION ARE NOT WELL UNDERSTOOD. EPIGENETICS PLAYS AN IMPORTANT ROLE IN THE CONTROL OF T CELL DEVELOPMENT, DIFFERENTIATION, AND FUNCTION. TO EXAMINE IF EPIGENETICS ALSO PLAYS A ROLE IN T CELL EXHAUSTION, WE ANALYZED CHROMATIN REMODELING IN CD8(+) T CELLS FROM MICE WITH CHRONIC LYMPHOCYTIC CHORIOMENINGITIS VIRUS INFECTION. WE OBSERVED DOWNREGULATION OF DIACETYLATED HISTONE H3 IN BOTH VIRUS-SPECIFIC AND TOTAL CD8(+) T CELLS, AND FUNCTIONAL DEFECTS NOT ONLY IN VIRUS-SPECIFIC CD8(+) T CELLS BUT ALSO WITHIN THE TOTAL CD8(+) T CELL POPULATION. IN VITRO TREATMENT OF THESE EXHAUSTED CD8(+) T CELLS WITH HISTONE DEACETYLASE INHIBITORS RESTORED DIACETYLATED HISTONE H3 LEVELS, AND IMPROVED THEIR IMMUNE FUNCTIONS. UPON ADOPTIVE TRANSFER, THESE TREATED CD8(+) T CELLS DEVELOPED INTO FUNCTIONAL MEMORY T CELLS IN VIVO THAT ENHANCED PROTECTIVE IMMUNITY. THESE RESULTS DEFINE A ROLE OF EPIGENETICS IN T CELL EXHAUSTION AND SUGGEST EPIGENETIC MANIPULATION AS A NOVEL MOLECULAR THERAPY TO RESTORE IMMUNE FUNCTIONS. 2014 10 1479 24 DIVERSE TARGETS OF THE TRANSCRIPTION FACTOR STAT3 CONTRIBUTE TO T CELL PATHOGENICITY AND HOMEOSTASIS. STAT3, AN ESSENTIAL TRANSCRIPTION FACTOR WITH PLEIOTROPIC FUNCTIONS, PLAYS CRITICAL ROLES IN THE PATHOGENESIS OF AUTOIMMUNITY. DESPITE RECENT DATA LINKING STAT3 WITH INFLAMMATORY BOWEL DISEASE, EXACTLY HOW IT CONTRIBUTES TO CHRONIC INTESTINAL INFLAMMATION IS NOT KNOWN. USING A T CELL TRANSFER MODEL OF COLITIS, WE FOUND THAT STAT3 EXPRESSION IN T CELLS WAS ESSENTIAL FOR THE INDUCTION OF BOTH COLITIS AND SYSTEMIC INFLAMMATION. STAT3 WAS CRITICAL IN MODULATING THE BALANCE OF T HELPER 17 (TH17) AND REGULATORY T (TREG) CELLS, AS WELL AS IN PROMOTING CD4(+) T CELL PROLIFERATION. WE USED CHROMATIN IMMUNOPRECIPITATION AND MASSIVE PARALLEL SEQUENCING (CHIP-SEQ) TO DEFINE THE GENOME-WIDE TARGETS OF STAT3 IN CD4(+) T CELLS. WE FOUND THAT STAT3 BOUND TO MULTIPLE GENES INVOLVED IN TH17 CELL DIFFERENTIATION, CELL ACTIVATION, PROLIFERATION, AND SURVIVAL, REGULATING BOTH EXPRESSION AND EPIGENETIC MODIFICATIONS. THUS, STAT3 ORCHESTRATES MULTIPLE CRITICAL ASPECTS OF T CELL FUNCTION IN INFLAMMATION AND HOMEOSTASIS. 2010 11 942 29 CHRONIC LYMPHOCYTIC LEUKEMIA PRESENCE IMPAIRS ANTIGEN-SPECIFIC CD8(+) T-CELL RESPONSES THROUGH EPIGENETIC REPROGRAMMING TOWARDS SHORT-LIVED EFFECTORS. T-CELL DYSREGULATION IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) ASSOCIATES WITH LOW RESPONSE RATES TO AUTOLOGOUS T CELL-BASED THERAPIES. HOW CLL AFFECTS ANTIGEN-SPECIFIC T-CELL RESPONSES REMAINS LARGELY UNKNOWN. WE INVESTIGATED (EPI)GENETIC AND FUNCTIONAL CONSEQUENCES OF ANTIGEN-SPECIFIC T-CELL RESPONSES IN PRESENCE OF CLL IN VITRO AND IN AN ADOPTIVE-TRANSFER MURINE MODEL. ALREADY AT STEADY-STATE, ANTIGEN-EXPERIENCED PATIENT-DERIVED T CELLS WERE SKEWED TOWARDS SHORT-LIVED EFFECTOR CELLS (SLEC) AT THE EXPENSE OF MEMORY-PRECURSOR EFFECTOR CELLS (MPEC). STIMULATION OF THESE T CELLS IN VITRO SHOWED RAPID INDUCTION OF EFFECTOR GENES AND SUPPRESSION OF KEY MEMORY TRANSCRIPTION FACTORS ONLY IN PRESENCE OF CLL CELLS, INDICATING EPIGENETIC REGULATION. THIS WAS INVESTIGATED IN VIVO BY FOLLOWING ANTIGEN-SPECIFIC RESPONSES OF NAIVE OT-I CD8(+) CELLS TO MCMV-OVA IN PRESENCE/ABSENCE OF TCL1 B-CELL LEUKEMIA. PRESENCE OF LEUKEMIA RESULTED IN INCREASED SLEC FORMATION, WITH DISTURBED INFLAMMATORY CYTOKINE PRODUCTION. CHROMATIN AND TRANSCRIPTOME PROFILING REVEALED STRONG EPIGENETIC MODIFICATIONS, LEADING TO ACTIVATION OF AN EFFECTOR AND SILENCING OF A MEMORY PROFILE THROUGH PRESENCE OF CLL CELLS. SECONDARY CHALLENGE IN VIVO CONFIRMED DYSFUNCTIONAL MEMORY RESPONSES BY ANTIGEN-EXPERIENCED OT-I CELLS GENERATED IN PRESENCE OF CLL. ALTOGETHER, WE SHOW THAT PRESENCE OF CLL INDUCES A SHORT-LIVED EFFECTOR PHENOTYPE AND IMPAIRED MEMORY RESPONSES BY EPIGENETIC REPROGRAMMING DURING PRIMARY RESPONSES. 2023 12 5972 21 TET REPRESSION AND INCREASED DNMT ACTIVITY SYNERGISTICALLY INDUCE ABERRANT DNA METHYLATION. CHRONIC INFLAMMATION IS DEEPLY INVOLVED IN VARIOUS HUMAN DISORDERS, SUCH AS CANCER, NEURODEGENERATIVE DISORDERS, AND METABOLIC DISORDERS. INDUCTION OF EPIGENETIC ALTERATIONS, ESPECIALLY ABERRANT DNA METHYLATION, IS ONE OF THE MAJOR MECHANISMS, BUT HOW IT IS INDUCED IS STILL UNCLEAR. HERE, WE FOUND THAT EXPRESSION OF TET GENES, METHYLATION ERASERS, WAS DOWNREGULATED IN INFLAMED MOUSE AND HUMAN TISSUES, AND THAT THIS WAS CAUSED BY UPREGULATION OF TET-TARGETING MIRNAS SUCH AS MIR20A, MIR26B, AND MIR29C, LIKELY DUE TO ACTIVATION OF NF-KAPPAB SIGNALING DOWNSTREAM OF IL-1BETA AND TNF-ALPHA. HOWEVER, TET KNOCKDOWN INDUCED ONLY MILD ABERRANT METHYLATION. NITRIC OXIDE (NO), PRODUCED BY NOS2, ENHANCED ENZYMATIC ACTIVITY OF DNA METHYLTRANSFERASES (DNMTS), METHYLATION WRITERS, AND NO EXPOSURE INDUCED MINIMAL ABERRANT METHYLATION. IN CONTRAST, A COMBINATION OF TET KNOCKDOWN AND NO EXPOSURE SYNERGISTICALLY INDUCED ABERRANT METHYLATION, INVOLVING GENOMIC REGIONS NOT METHYLATED BY EITHER ALONE. THE RESULTS SHOWED THAT A VICIOUS COMBINATION OF TET REPRESSION, DUE TO NF-KAPPAB ACTIVATION, AND DNMT ACTIVATION, DUE TO NO PRODUCTION, IS RESPONSIBLE FOR ABERRANT METHYLATION INDUCTION IN HUMAN TISSUES. 2020 13 556 32 AZACYTIDINE TREATMENT INHIBITS THE PROGRESSION OF HERPES STROMAL KERATITIS BY ENHANCING REGULATORY T CELL FUNCTION. OCULAR INFECTION WITH HERPES SIMPLEX VIRUS 1 (HSV-1) SETS OFF AN INFLAMMATORY REACTION IN THE CORNEA WHICH LEADS TO BOTH VIRUS CLEARANCE AND CHRONIC LESIONS THAT ARE ORCHESTRATED BY CD4 T CELLS. APPROACHES THAT ENHANCE THE FUNCTION OF REGULATORY T CELLS (TREG) AND DAMPEN EFFECTOR T CELLS CAN BE EFFECTIVE TO LIMIT STROMAL KERATITIS (SK) LESION SEVERITY. IN THIS REPORT, WE EXPLORE THE NOVEL APPROACH OF INHIBITING DNA METHYLTRANSFERASE ACTIVITY USING 5-AZACYTIDINE (AZA; A CYTOSINE ANALOG) TO LIMIT HSV-1-INDUCED OCULAR LESIONS. WE SHOW THAT THERAPY BEGUN AFTER INFECTION WHEN VIRUS WAS NO LONGER ACTIVELY REPLICATING RESULTED IN A PRONOUNCED REDUCTION IN LESION SEVERITY, WITH MARKEDLY DIMINISHED NUMBERS OF T CELLS AND NONLYMPHOID INFLAMMATORY CELLS, ALONG WITH REDUCED CYTOKINE MEDIATORS. THE REMAINING INFLAMMATORY REACTIONS HAD A CHANGE IN THE RATIO OF CD4 FOXP3(+) TREG TO EFFECTOR TH1 CD4 T CELLS IN OCULAR LESIONS AND LYMPHOID TISSUES, WITH TREG BECOMING PREDOMINANT OVER THE EFFECTORS. IN ADDITION, COMPARED TO THOSE FROM CONTROL MICE, TREG FROM AZA-TREATED MICE SHOWED MORE SUPPRESSOR ACTIVITY IN VITRO AND EXPRESSED HIGHER LEVELS OF ACTIVATION MOLECULES. ADDITIONALLY, CELLS INDUCED IN VITRO IN THE PRESENCE OF AZA SHOWED EPIGENETIC DIFFERENCES IN THE TREG-SPECIFIC DEMETHYLATED REGION (TSDR) OF FOXP3 AND WERE MORE STABLE WHEN EXPOSED TO INFLAMMATORY CYTOKINES. OUR RESULTS SHOW THAT THERAPY WITH AZA IS AN EFFECTIVE MEANS OF CONTROLLING A VIRUS-INDUCED INFLAMMATORY REACTION AND MAY ACT MAINLY BY THE EFFECTS ON TREG.IMPORTANCE HSV-1 INFECTION HAS BEEN SHOWN TO INITIATE AN INFLAMMATORY REACTION IN THE CORNEA THAT LEADS TO TISSUE DAMAGE AND LOSS OF VISION. THE INFLAMMATORY REACTION IS ORCHESTRATED BY GAMMA INTERFERON (IFN-GAMMA)-SECRETING TH1 CELLS, AND REGULATORY T CELLS PLAY A PROTECTIVE ROLE. HENCE, NOVEL THERAPEUTICS THAT CAN REBALANCE THE RATIO OF REGULATORY T CELLS TO EFFECTORS ARE A RELEVANT ISSUE. THIS STUDY OPENS UP A NEW AVENUE IN TREATING HSV-INDUCED SK LESIONS BY INCREASING THE STABILITY AND FUNCTION OF REGULATORY T CELLS USING THE DNA METHYLTRANSFERASE INHIBITOR 5-AZACYTIDINE (AZA). AZA INCREASED THE FUNCTION OF REGULATORY T CELLS, LEADING TO ENHANCED SUPPRESSIVE ACTIVITY AND DIMINISHED LESIONS. HENCE, THERAPY WITH AZA, WHICH ACTS MAINLY BY ITS EFFECTS ON TREG, CAN BE AN EFFECTIVE MEANS TO CONTROL VIRUS-INDUCED INFLAMMATORY LESIONS. 2017 14 2002 25 EPIGENETIC AND POST-TRANSCRIPTIONAL REPRESSION SUPPORT METABOLIC SUPPRESSION IN CHRONICALLY HYPOXIC GOLDFISH. GOLDFISH ENTER A HYPOMETABOLIC STATE TO SURVIVE CHRONIC HYPOXIA. WE RECENTLY DESCRIBED TISSUE-SPECIFIC CONTRIBUTIONS OF MEMBRANE LIPID COMPOSITION REMODELING AND MITOCHONDRIAL FUNCTION TO METABOLIC SUPPRESSION ACROSS DIFFERENT GOLDFISH TISSUES. HOWEVER, THE MOLECULAR AND ESPECIALLY EPIGENETIC FOUNDATIONS OF HYPOXIA TOLERANCE IN GOLDFISH UNDER METABOLIC SUPPRESSION ARE NOT WELL UNDERSTOOD. HERE WE SHOW THAT COMPONENTS OF THE MOLECULAR OXYGEN-SENSING MACHINERY ARE ROBUSTLY ACTIVATED ACROSS TISSUES IRRESPECTIVE OF HYPOXIA DURATION. INDUCTION OF GENE EXPRESSION OF ENZYMES INVOLVED IN DNA METHYLATION TURNOVER AND MICRORNA BIOGENESIS SUGGEST A ROLE FOR EPIGENETIC TRANSCRIPTIONAL AND POST-TRANSCRIPTIONAL SUPPRESSION OF GENE EXPRESSION IN THE HYPOXIA-ACCLIMATED BRAIN. CONVERSELY, MECHANISTIC TARGET OF RAPAMYCIN-DEPENDENT TRANSLATIONAL MACHINERY ACTIVITY IS NOT REDUCED IN LIVER AND WHITE MUSCLE, SUGGESTING THIS PATHWAY DOES NOT CONTRIBUTE TO LOWERING CELLULAR ENERGY EXPENDITURE. FINALLY, MOLECULAR EVIDENCE SUPPORTS PREVIOUSLY REPORTED CHRONIC HYPOXIA-DEPENDENT CHANGES IN MEMBRANE CHOLESTEROL, LIPID METABOLISM AND MITOCHONDRIAL FUNCTION VIA CHANGES IN TRANSCRIPTS INVOLVED IN CHOLESTEROL BIOSYNTHESIS, BETA-OXIDATION, AND MITOCHONDRIAL FUSION IN MULTIPLE TISSUES. OVERALL, THIS STUDY SHOWS THAT CHRONIC HYPOXIA ROBUSTLY INDUCES EXPRESSION OF OXYGEN-SENSING MACHINERY ACROSS TISSUES, INDUCES REPRESSIVE TRANSCRIPTIONAL AND POST-TRANSCRIPTIONAL EPIGENETIC MARKS ESPECIALLY IN THE CHRONIC HYPOXIA-ACCLIMATED BRAIN AND SUPPORTS A ROLE FOR MEMBRANE REMODELING AND MITOCHONDRIAL FUNCTION AND DYNAMICS IN PROMOTING METABOLIC SUPPRESSION. 2022 15 3662 29 INDUCTION OF STABLE HUMAN FOXP3(+) TREGS BY A PARASITE-DERIVED TGF-BETA MIMIC. IMMUNE HOMEOSTASIS IN THE INTESTINE IS TIGHTLY CONTROLLED BY FOXP3(+) REGULATORY T CELLS (TREGS), DEFECTS OF WHICH ARE LINKED TO THE DEVELOPMENT OF CHRONIC CONDITIONS, SUCH AS INFLAMMATORY BOWEL DISEASE (IBD). AS A MECHANISM OF IMMUNE EVASION, SEVERAL SPECIES OF INTESTINAL PARASITES BOOST TREG ACTIVITY. THE PARASITE HELIGMOSOMOIDES POLYGYRUS IS KNOWN TO SECRETE A MOLECULE (HP-TGM) THAT MIMICS THE ABILITY OF TGF-BETA TO INDUCE FOXP3 EXPRESSION IN CD4(+) T CELLS. THE STUDY AIMED TO INVESTIGATE WHETHER HP-TGM COULD INDUCE HUMAN FOXP3(+) TREGS AS A POTENTIAL THERAPEUTIC APPROACH FOR INFLAMMATORY DISEASES. CD4(+) T CELLS FROM HEALTHY VOLUNTEERS WERE EXPANDED IN THE PRESENCE OF HP-TGM OR TGF-BETA. TREG INDUCTION WAS MEASURED BY FLOW CYTOMETRIC DETECTION OF FOXP3 AND OTHER TREG MARKERS, SUCH AS CD25 AND CTLA-4. EPIGENETIC CHANGES WERE DETECTED USING CHIP-SEQ AND PYROSEQUENCING OF FOXP3. TREG PHENOTYPE STABILITY WAS ASSESSED FOLLOWING INFLAMMATORY CYTOKINE CHALLENGE AND TREG FUNCTION WAS EVALUATED BY CELLULAR CO-CULTURE SUPPRESSION ASSAYS AND CYTOMETRIC BEAD ARRAYS FOR SECRETED CYTOKINES. HP-TGM EFFICIENTLY INDUCED FOXP3 EXPRESSION (> 60%), IN ADDITION TO CD25 AND CTLA-4, AND CAUSED EPIGENETIC MODIFICATION OF THE FOXP3 LOCUS TO A GREATER EXTENT THAN TGF-BETA. HP-TGM-INDUCED TREGS HAD SUPERIOR SUPPRESSIVE FUNCTION COMPARED WITH TGF-BETA-INDUCED TREGS, AND RETAINED THEIR PHENOTYPE FOLLOWING EXPOSURE TO INFLAMMATORY CYTOKINES. FURTHERMORE, HP-TGM INDUCED A TREG-LIKE PHENOTYPE IN IN VIVO DIFFERENTIATED TH1 AND TH17 CELLS, INDICATING ITS POTENTIAL TO RE-PROGRAM MEMORY CELLS TO ENHANCE IMMUNE TOLERANCE. THESE DATA INDICATE HP-TGM HAS POTENTIAL TO BE USED TO GENERATE STABLE HUMAN FOXP3(+) TREGS TO TREAT IBD AND OTHER INFLAMMATORY DISEASES. 2021 16 3167 33 GROUP 1 METABOTROPIC GLUTAMATE RECEPTOR EXPRESSION DEFINES A T CELL MEMORY POPULATION DURING CHRONIC TOXOPLASMA INFECTION THAT ENHANCES IFN-GAMMA AND PERFORIN PRODUCTION IN THE CNS. WITHIN THE BRAIN, A PRO-INFLAMMATORY RESPONSE IS ESSENTIAL TO PREVENT CLINICAL DISEASE DUE TO TOXOPLASMA GONDII REACTIVATION. INFECTION IN THE IMMUNOCOMPROMISED LEADS TO LETHAL TOXOPLASMIC ENCEPHALITIS WHILE IN THE IMMUNOCOMPETENT, THERE IS PERSISTENT LOW-GRADE INFLAMMATION WHICH IS DEVOID OF CLINICAL SYMPTOMS. THIS SIGNIFIES THAT THERE IS A WELL-BALANCED AND REGULATED INFLAMMATORY RESPONSE TO T. GONDII IN THE BRAIN. T CELLS ARE THE DOMINANT IMMUNE CELLS THAT PREVENT CLINICAL DISEASE, AND THIS IS MEDIATED THROUGH THE SECRETION OF EFFECTOR MOLECULES SUCH AS PERFORINS AND IFN-GAMMA. THE PRESENCE OF COGNATE ANTIGEN, THE EXPRESSION OF SURVIVAL CYTOKINES, AND THE ALTERATION OF THE EPIGENETIC LANDSCAPE DRIVE THE DEVELOPMENT OF MEMORY T CELLS. HOWEVER, SPECIFIC EXTRINSIC SIGNALS THAT PROMOTE THE FORMATION AND MAINTENANCE OF MEMORY T CELLS WITHIN TISSUE ARE POORLY UNDERSTOOD. DURING CHRONIC INFECTION, THERE IS AN INCREASE IN EXTRACELLULAR GLUTAMATE THAT, DUE TO ITS FUNCTION AS AN EXCITATORY NEUROTRANSMITTER, IS NORMALLY TIGHTLY CONTROLLED IN THE CNS. HERE WE DEMONSTRATE THAT CD8(+) T CELLS FROM THE T. GONDII-INFECTED BRAIN PARENCHYMA ARE ENRICHED FOR METABOTROPIC GLUTAMATE RECEPTORS (MGLUR'S). CHARACTERIZATION STUDIES DETERMINED THAT MGLUR(+) EXPRESSION BY CD8(+) T CELLS DEFINES A DISTINCT MEMORY POPULATION AT THE TRANSCRIPTIONAL AND PROTEIN LEVEL. FINALLY, USING RECEPTOR ANTAGONISTS AND AGONISTS WE DEMONSTRATE MGLUR SIGNALING IS REQUIRED FOR OPTIMAL CD8(+) T CELL PRODUCTION OF THE EFFECTOR CYTOKINE IFNGAMMA. THIS WORK SUGGESTS THAT GLUTAMATE IS AN IMPORTANT ENVIRONMENTAL SIGNAL OF INFLAMMATION THAT PROMOTES T CELL FUNCTION. UNDERSTANDING GLUTAMATE'S INFLUENCE ON T CELLS IN THE BRAIN CAN PROVIDE INSIGHTS INTO THE MECHANISMS THAT GOVERN PROTECTIVE IMMUNITY AGAINST CNS-INFILTRATING PATHOGENS AND NEUROINFLAMMATION. 2023 17 1594 25 DNA METHYLATION PROFILING REVEALS DIFFERENCES IN THE 3 HUMAN MONOCYTE SUBSETS AND IDENTIFIES UREMIA TO INDUCE DNA METHYLATION CHANGES DURING DIFFERENTIATION. HUMAN MONOCYTES ARE A HETEROGENEOUS CELL POPULATION CONSISTING OF 3 SUBSETS: CLASSICAL CD14++CD16-, INTERMEDIATE CD14++CD16+ AND NONCLASSICAL CD14+CD16++ MONOCYTES. VIA POORLY CHARACTERIZED MECHANISMS, INTERMEDIATE MONOCYTE COUNTS RISE IN CHRONIC INFLAMMATORY DISEASES, AMONG WHICH CHRONIC KIDNEY DISEASE IS OF PARTICULAR EPIDEMIOLOGIC IMPORTANCE. DNA METHYLATION IS A CENTRAL EPIGENETIC FEATURE THAT CONTROLS HEMATOPOIESIS. BY APPLYING NEXT-GENERATION METHYL-SEQUENCING WE NOW TESTED HOW FAR THE 3 MONOCYTE SUBSETS DIFFER IN THEIR DNA METHYLOME AND WHETHER UREMIA INDUCES DNA METHYLATION CHANGES IN DIFFERENTIATING MONOCYTES. WE FOUND THAT EACH MONOCYTE SUBSET DISPLAYS A UNIQUE PHENOTYPE WITH REGARDS TO DNA METHYLATION. GENES WITH DIFFERENTIALLY METHYLATED PROMOTER REGIONS IN INTERMEDIATE MONOCYTES WERE LINKED TO DISTINCT IMMUNOLOGICAL PROCESSES, WHICH IS IN LINE WITH RESULTS FROM RECENT GENE EXPRESSION ANALYSES. IN VITRO, UREMIA INDUCED DYSREGULATION OF DNA METHYLATION IN DIFFERENTIATING MONOCYTES, WHICH AFFECTED SEVERAL TRANSCRIPTION REGULATORS IMPORTANT FOR MONOCYTE DIFFERENTIATION (E.G., FLT3, HDAC1, MNT) AND LED TO ENHANCED GENERATION OF INTERMEDIATE MONOCYTES. AS POTENTIAL MEDIATOR, THE UREMIC TOXIN AND METHYLATION INHIBITOR S-ADENOSYLHOMOCYSTEINE INDUCED SHIFTS IN MONOCYTE SUBSETS IN VITRO, AND ASSOCIATED WITH MONOCYTE SUBSET COUNTS IN VIVO. OUR DATA SUPPORT THE CONCEPT OF MONOCYTE TRICHOTOMY AND THE DISTINCT ROLE OF INTERMEDIATE MONOCYTES IN HUMAN IMMUNITY. THE SHIFT IN MONOCYTE SUBSETS THAT OCCURS IN CHRONIC KIDNEY DISEASE, A PROINFLAMMATORY CONDITION OF SUBSTANTIAL EPIDEMIOLOGICAL IMPACT, MAY BE INDUCED BY ACCUMULATION OF UREMIC TOXINS THAT MEDIATE EPIGENETIC DYSREGULATION. 2016 18 2055 19 EPIGENETIC CONTROL DURING LYMPHOID DEVELOPMENT AND IMMUNE RESPONSES: ABERRANT REGULATION, VIRUSES, AND CANCER. METHYLATION OF CYTOSINES CONTROLS A NUMBER OF BIOLOGIC PROCESSES SUCH AS IMPRINTING AND X CHROMOSOMAL INACTIVATION. DNA HYPERMETHYLATION IS CLOSELY ASSOCIATED WITH TRANSCRIPTIONAL SILENCING, WHILE DNA HYPOMETHYLATION IS ASSOCIATED WITH TRANSCRIPTIONAL ACTIVATION. HYPOACETYLATION OF HISTONES LEADS TO COMPACT CHROMATIN WITH REDUCED ACCESSIBILITY TO THE TRANSCRIPTIONAL MACHINERY. METHYL-CPG BINDING PROTEINS CAN RECRUIT COREPRESSORS AND HISTONE DEACETYLASES; THUS, THE INTERPLAY BETWEEN THESE EPIGENETIC MECHANISMS REGULATES GENE ACTIVATION. METHYLATION HAS BEEN IMPLICATED AS AN IMPORTANT MECHANISM DURING IMMUNE DEVELOPMENT, CONTROLLING VDJ RECOMBINATION, LINEAGE-SPECIFIC EXPRESSION OF CELL SURFACE ANTIGENS, AND TRANSCRIPTIONAL REGULATION OF CYTOKINE GENES DURING IMMUNE RESPONSES. ABERRATIONS IN EPIGENETIC MACHINERY, EITHER BY GENETIC MUTATIONS OR BY SOMATIC CHANGES SUCH AS VIRAL INFECTIONS, ARE ASSOCIATED WITH EARLY ALTERATIONS IN CHRONIC DISEASES SUCH AS IMMUNODEFICIENCY AND CANCER. 2003 19 3948 30 LNCRNA-CD160 DECREASES THE IMMUNITY OF CD8(+) T CELLS THROUGH EPIGENETIC MECHANISMS IN HEPATITIS B VIRUS INFECTION. THE TRANSFER AND DEVELOPMENT OF CHRONIC HEPATITIS B VIRUS (HBV) INFECTION IS ASSOCIATED WITH THE T CELL IMMUNE RESPONSE, THEREFORE INVESTIGATING THE KEY REGULATORS OF CELL IMMUNE RESPONSE IS NEEDED TO IMPROVE CHRONIC HBV TREATMENT. BLOOD SAMPLES FROM PATIENTS WITH CHRONIC HBV INFECTION WERE USED TO CONFIRM THE CORRELATION BETWEEN HBV INFECTION STAGE AND CD160 RECEPTOR EXPRESSION LEVELS IN CD8(+) T CELLS, THE CD8(+) T CELLS ARE USED TO RESEARCH THE MECHANISM OF T CELL IMMUNE RESPONSE MODULATION, MOREOVER, C3H/HEN MICE WITH REDUCED CD160 EXPRESSION LEVELS WERE USED TO INVESTIGATE THE ASSOCIATION BETWEEN LONG NON-CODING (LNC)RNA-CD160 AND HBV INFECTION. LONG NON-CODING (LNC)RNA-CD160 AND HISTONE-MODIFICATION ENZYME GENE HISTONE DEACETYLASE 11 (HDAC11) EXPRESSION LEVELS WERE NEGATIVELY ASSOCIATED WITH CD160 EXPRESSION. LNCRNA-CD160 CAN INHIBIT THE SECRETION OF IFN-GAMMA AND TNF-ALPHA THROUGH HDAC11 RECRUITMENT AND BIND TO HDAC11 TO FORM A COMPLEX ON THE PROMOTERS OF IFN-GAMMA AND TNF-ALPHA. THE HDAC11, IFN-GAMMA AND TNF-ALPHA FORM A COMPLEX AND ENHANCE THE METHYLATION OF H3K9ME1, CHROMATIN CHANGES INTO THE HETEROCHROMATIN AND THE TRANSCRIPTION OF IFN-GAMMA AND TNF-ALPHA IS BLOCKED; MOREOVER, THE HDAC11/IFN-GAMMA/TNF-ALPHA COMPLEX CAN ALSO INHIBIT THE SECRETION OF IFN-GAMMA AND TNF-ALPHA IN CD160(-) CD8(+) T CELLS AND SUPPRESSES THE FUNCTION OF CD8(+) T CELLS. FURTHERMORE, SMALL INTERFERING RNA TARGETING LNCRNA-CD160 CAN BLOCK HBV INFECTION PROGRESSION. LNCRNA-CD160 ACTS AS AN IMMUNE SUPPRESSIVE FACTOR AND IS EXPRESSED AT A HIGH LEVEL IN PERIPHERAL BLOOD CD8(+) T CELLS OF HBV INFECTED PATIENTS. FURTHERMORE, HIGH EXPRESSION LEVELS OF LNCRNA-CD160 CAN CONTRIBUTE TO THE INHIBITION OF IFN-GAMMA AND TNF-ALPHA SECRETION IN CD8(+) T CELLS AND DECREASE THE IMMUNE RESPONSE OF CD8(+) T CELLS. THEREFORE, LNCRNA-CD160 MAY BECOME A NEW TARGET FOR IMMUNOTHERAPY OF CHRONIC HBV INFECTION IN THE FUTURE AND MAY PROVIDE A NEW THERAPEUTIC STRATEGY FOR THE TREATMENT OF HBV INFECTION. 2020 20 3525 24 IL-1BETA, IL-8, AND MATRIX METALLOPROTEINASES-1, -2, AND -10 ARE ENRICHED UPON MONOCYTE-BREAST CANCER CELL COCULTIVATION IN A MATRIGEL-BASED THREE-DIMENSIONAL SYSTEM. BREAST CANCER REMAINS THE FIRST CANCER-RELATED CAUSE OF DEATH IN WOMEN WORLDWIDE, PARTICULARLY IN DEVELOPING COUNTRIES IN WHICH MOST CASES ARE DIAGNOSED IN LATE STAGES. ALTHOUGH MOST CANCER STUDIES ARE BASED IN THE GENETIC OR EPIGENETIC CHANGES OF THE TUMOR CELLS, IMMUNE CELLS WITHIN THE TUMOR STROMA OFTEN COOPERATE WITH CANCER PROGRESSION. PARTICULARLY, MONOCYTES ARE ATTRACTED TO THE TUMOR PRIMARY SITE IN WHICH THEY ARE DIFFERENTIATED INTO TUMOR-ASSOCIATED MACROPHAGES THAT FACILITATE TUMOR CELL INVASION AND METASTASIS. IN THIS STUDY, WE USED THREE-DIMENSIONAL CULTURES TO FORM ACINI-LIKE STRUCTURES TO ANALYZE THE INFLAMMATORY SECRETION PROFILE OF TUMOR CELLS INDIVIDUALLY OR IN CO-CULTURE WITH MONOCYTES. BREAST CANCER CELL LINES AND PRIMARY ISOLATES FROM EIGHT MEXICAN PATIENTS WITH BREAST CANCER WERE USED. WE FOUND HIGH LEVELS OF RANTES/CCL5, MCP-1/CCL2, AND G-CSF IN THE BREAST CANCER INDIVIDUAL CULTURES, SUPPORTING AN IMPORTANT RECRUITMENT CAPACITY OF MONOCYTES, BUT ALSO OF NEUTROPHILS. THE CO-CULTURES OF THE TUMOR CELLS AND MONOCYTES WERE SIGNIFICANTLY ENRICHED WITH THE POTENT PRO-INFLAMMATORY CYTOKINES INTERLEUKIN (IL)-1BETA AND IL-8, KNOWN TO SUPPORT MALIGNANT PROGRESSION. WE ALSO FOUND THAT THE INTERACTION OF TUMOR CELLS WITH MONOCYTES PROMOTED HIGH LEVELS OF MATRIX METALLOPROTEINASES (MMP)-1, MMP-2, AND MMP-10. OUR STUDY SUPPORTS THAT A KEY EVENT FOR MALIGNANT PROGRESSION IS THE RECRUITMENT OF DIFFERENT IMMUNE CELL POPULATIONS, WHICH HELP TO SUSTAIN AND ENHANCE A CHRONIC INFLAMMATORY MICROENVIRONMENT THAT HIGHLY FAVORS TUMOR MALIGNANCY. 2017