1 3167 145 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 2 6057 26 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 3 5872 32 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 4 6530 40 TRANSCRIPTIONAL REGULATION AND T CELL EXHAUSTION. PURPOSE OF REVIEW: THIS REVIEW HIGHLIGHTS THE CONTROL OF TRANSCRIPTIONAL NETWORKS, INCLUDING INDUCTION OF INHIBITORY RECEPTORS, BY T CELL-SPECIFIC TRANSCRIPTION FACTORS IN EXHAUSTED T CELLS THAT ACCUMULATE IN CHRONIC VIRAL INFECTIONS INCLUDING HIV. RECENT FINDINGS: TRANSCRIPTIONAL PROFILING HAS ESTABLISHED DISTINCT MOLECULAR PHENOTYPES FOR EXHAUSTED CD4 AND CD8 T CELLS IN CHRONIC VIRAL INFECTION MODELS. THERE EXISTS A SUBSET OF TRANSCRIPTION FACTORS ASSOCIATED WITH EXHAUSTION, NOTABLY BLIMP-1, BASIC LEUCINE ZIPPER TRANSCRIPTION FACTOR, ATF-LIKE AND HELIOS. EPIGENETIC PHENOMENA ARE LIKELY IMPORTANT IN REGULATING GENE EXPRESSION NETWORKS DURING EXHAUSTION AS ILLUSTRATED BY PROGRAMMED DEATH 1 PROMOTER METHYLATION PATTERNS. SUMMARY: FOLLOWING CHRONIC VIRAL INFECTIONS, CD4 AND CD8 T CELLS DEFINED FUNCTIONALLY AND PHENOTYPICALLY AS EXHAUSTED HAVE DISTINCT TRANSCRIPTIONAL PROFILES. THESE STUDIES HAVE IDENTIFIED A CORE SET OF TRANSCRIPTION FACTORS THAT HAVE BEEN IMPLICATED IN PROMOTING EXHAUSTION. HOWEVER, NO SINGLE FACTOR APPEARS TO BE AN EXHAUSTION DETERMINING FACTOR, SUGGESTING THAT T CELL EXHAUSTION REFLECTS A COMBINATORIAL MECHANISM WITH MULTIPLE TRANSCRIPTION FACTORS INTERACTING TO INFLUENCE THE DEVELOPMENT OF FUNCTIONALLY EXHAUSTED T CELLS AS WELL AS DIFFERENT T EFFECTOR POPULATIONS. 2014 5 2146 35 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 6 2056 31 EPIGENETIC CONTROL OF CD8(+) T CELL DIFFERENTIATION. UPON STIMULATION, SMALL NUMBERS OF NAIVE CD8(+) T CELLS PROLIFERATE AND DIFFERENTIATE INTO A VARIETY OF MEMORY AND EFFECTOR CELL TYPES. CD8(+) T CELLS CAN PERSIST FOR YEARS AND KILL TUMOUR CELLS AND VIRALLY INFECTED CELLS. THE FUNCTIONAL AND PHENOTYPIC CHANGES THAT OCCUR DURING CD8(+) T CELL DIFFERENTIATION ARE WELL CHARACTERIZED, BUT THE EPIGENETIC STATES THAT UNDERLIE THESE CHANGES ARE INCOMPLETELY UNDERSTOOD. HERE, WE REVIEW THE EPIGENETIC PROCESSES THAT DIRECT CD8(+) T CELL DIFFERENTIATION AND FUNCTION. WE FOCUS ON EPIGENETIC MODIFICATION OF DNA AND ASSOCIATED HISTONES AT GENES AND THEIR REGULATORY ELEMENTS. WE ALSO DESCRIBE STRUCTURAL CHANGES IN CHROMATIN ORGANIZATION THAT AFFECT GENE EXPRESSION. FINALLY, WE EXAMINE THE TRANSLATIONAL POTENTIAL OF EPIGENETIC INTERVENTIONS TO IMPROVE CD8(+) T CELL FUNCTION IN INDIVIDUALS WITH CHRONIC INFECTIONS AND CANCER. 2018 7 5130 33 POSTTRANSCRIPTIONAL GENE REGULATION: NOVEL PATHWAYS FOR GLUCOCORTICOIDS' ANTI-INFLAMMATORY ACTION. POSTTRANSCRIPTIONAL GENE REGULATION (PTR) IS A FUNDAMENTAL BIOLOGICAL PROCESS THAT INTEGRATES WITH THE MASTER TRANSCRIPTIONAL CONTROL OF GENE EXPRESSION, IN WAYS THAT ONLY IN THE LAST DECADE HAVE BEEN INCREASINGLY UNDERSTOOD [1, 2]. WHILE EPIGENETIC AND TRANSCRIPTIONAL EVENTS SHAPE CELL RESPONSE QUALITATIVELY, DECIDING THE PATTERN OF GENE EXPRESSION TO 'SWITCH ON OR OFF' IN RESPONSE TO ENDOGENOUS OR ENVIRONMENTAL TRIGGERS, THE KEY TASK OF PTR IS TO ACT AS A 'RHEOSTAT' AND RAPIDLY ADAPT THE CELLULAR RESPONSE BY PROVIDING THE APPROPRIATE AMPLITUDE AND TIMING TO THE PROTEIN EXPRESSION PATTERNS [3, 4]. THE PIVOTAL ROLE OF THIS MECHANISM COMES TO THE FOREFRONT IN INFLAMMATORY AND IMMUNE RESPONSE, WHERE THE CHANGES IN AMPLITUDE AND DURATION IN THE EXPRESSION OF DANGEROUS AND PROTECTIVE GENES ARE IN DELICATE BALANCE, AND ARE CRITICAL IN DETERMINING EITHER THE SUCCESSFUL RESOLUTION OF THE IMMUNE RESPONSE OR ITS CHRONIC OVEREXPRESSION [5]. THIS BRIEF REVIEW INTRODUCES MEMBERS OF THE MAIN CLASSES OF MOLECULES MEDIATING THE CYTOPLASMIC ARM OF GENE REGULATION, NAMELY RNA-BINDING PROTEINS AND MICRO-RNA (MIRNA), AND SUMMARIZES EXPERIMENTAL DATA THAT UNDERSCORE THE ROLE OF THESE MOLECULES IN THE PATHOPHYSIOLOGY OF CHRONIC INFLAMMATION, AS WELL AS THEIR PROMISING VALUE AS MECHANISMS CONVEYING THE ANTI-INFLAMMATORY EFFECT OF SYNTHETIC GLUCOCORTICOIDS. 2012 8 5414 42 REGULATION OF CD8(+) T MEMORY AND EXHAUSTION BY THE MTOR SIGNALS. CD8(+) T CELLS ARE THE KEY EXECUTIONERS OF THE ADAPTIVE IMMUNE ARM, WHICH MEDIATES ANTITUMOR AND ANTIVIRAL IMMUNITY. NAIVE CD8(+) T CELLS DEVELOP IN THE THYMUS AND ARE QUICKLY ACTIVATED IN THE PERIPHERY AFTER ENCOUNTERING A COGNATE ANTIGEN, WHICH INDUCES THESE CELLS TO PROLIFERATE AND DIFFERENTIATE INTO EFFECTOR CELLS THAT FIGHT THE INITIAL INFECTION. SIMULTANEOUSLY, A FRACTION OF THESE CELLS BECOME LONG-LIVED MEMORY CD8(+) T CELLS THAT COMBAT FUTURE INFECTIONS. NOTABLY, THE GENERATION AND MAINTENANCE OF MEMORY CELLS IS PROFOUNDLY AFFECTED BY VARIOUS IN VIVO CONDITIONS, SUCH AS THE MODE OF PRIMARY ACTIVATION (E.G., ACUTE VS. CHRONIC IMMUNIZATION) OR FLUCTUATIONS IN HOST METABOLIC, INFLAMMATORY, OR AGING FACTORS. THEREFORE, MANY T CELLS MAY BE LOST OR BECOME EXHAUSTED AND NO LONGER FUNCTIONAL. COMPLICATED INTRACELLULAR SIGNALING PATHWAYS, TRANSCRIPTION FACTORS, EPIGENETIC MODIFICATIONS, AND METABOLIC PROCESSES ARE INVOLVED IN THIS PROCESS. THEREFORE, UNDERSTANDING THE CELLULAR AND MOLECULAR BASIS FOR THE GENERATION AND FATE OF MEMORY AND EXHAUSTED CD8(+) CELLS IS CENTRAL FOR HARNESSING CELLULAR IMMUNITY. IN THIS REVIEW, WE FOCUS ON MAMMALIAN TARGET OF RAPAMYCIN (MTOR), PARTICULARLY SIGNALING MEDIATED BY MTOR COMPLEX (MTORC) 2 IN MEMORY AND EXHAUSTED CD8(+) T CELLS AT THE MOLECULAR LEVEL. 2023 9 198 43 ACQUIRED TRANSCRIPTIONAL PROGRAMMING IN FUNCTIONAL AND EXHAUSTED VIRUS-SPECIFIC CD8 T CELLS. PURPOSE OF REVIEW: FAILURE TO CONTROL VIRAL INFECTIONS SUCH AS HIV RESULTS IN T-CELL RECEPTOR (TCR) AND INHIBITORY RECEPTOR DRIVEN EXHAUSTION OF ANTIGEN-SPECIFIC T CELLS. PERSISTENT SIGNALING BY THESE RECEPTORS DURING CHRONIC VIRAL INFECTION SCULPTS THE TRANSCRIPTIONAL REGULATORY PROGRAMS OF VIRUS-SPECIFIC T CELLS. THE RESULTING GENE EXPRESSION PROFILE IS TAILORED TO TEMPER THE POTENTIALLY DAMAGING EFFECTOR FUNCTIONS OF CYTOTOXIC T CELLS AND ADAPT THEM TO AN ANTIGEN-RICH AND INFLAMMATION-RICH ENVIRONMENT. HERE WE REVIEW RECENT STUDIES INVESTIGATING MECHANISMS OF TRANSCRIPTIONAL REGULATION OF EFFECTOR, FUNCTIONAL MEMORY, AND EXHAUSTED T-CELL FUNCTIONS DURING ACUTE VERSUS CHRONIC INFECTIONS. RECENT FINDINGS: PATTERNS OF GENE EXPRESSION IN VIRUS-SPECIFIC CD8 T CELLS ARE A RESULT OF A COMBINATION OF PRO AND INHIBITORY SIGNALS FROM ANTIGEN PRESENTATION (TCR-MEDIATED) AND CO-INHIBITORY RECEPTOR LIGATION (PD-1, 2B4). FURTHER, MEMORY-SPECIFIC TRANSCRIPTIONAL REGULATION OF 2B4 EXPRESSION AND SIGNALING IMPOSE A SELF-LIMITING SECONDARY EFFECTOR RESPONSE TO A PROLONGED VIRAL INFECTION. ADDITIONALLY, DIFFERENTIATION OF FUNCTIONAL MEMORY CD8 T CELLS IS COUPLED WITH ACQUISITION OF A REPRESSIVE EPIGENETIC PROGRAM FOR PD-1 EXPRESSION. HOWEVER, CHRONIC INFECTION PROVIDES A SIGNAL THAT BLOCKS THE ACQUISITION OF THESE EPIGENETIC MODIFICATIONS REINFORCING THE SUPPRESSION OF CYTOTOXIC LYMPHOCYTE (CTL) FUNCTIONS IN EXHAUSTED CELLS. SUMMARY: CURRENT FINDINGS SUGGEST THAT THE MECHANISM(S) THAT DELINEATE FUNCTIONAL MEMORY VERSUS EXHAUSTION ARE COUPLED WITH ACQUISITION OF TRANSCRIPTIONAL PROGRAMS AT THE EFFECTOR STAGE OF DIFFERENTIATION, REINFORCED BY CESSATION OR PERSISTENCE OF TCR SIGNALING. 2012 10 2718 42 EXHAUSTED T CELLS AND EPIGENETIC STATUS. EXHAUSTED T CELLS ARE A GROUP OF DYSFUNCTIONAL T CELLS, WHICH ARE PRESENT IN CHRONIC INFECTIONS OR TUMORS. THE MOST SIGNIFICANT CHARACTERISTICS OF EXHAUSTED T CELLS ARE ATTENUATED EFFECTOR CYTOTOXICITY, REDUCED CYTOKINE PRODUCTION, AND UPREGULATION OF MULTIPLE INHIBITORY MOLECULAR RECEPTORS (E.G., PD-1, TIM-3, AND LAG-3). THE INTRACELLULAR METABOLIC CHANGES, ALTERED EXPRESSION OF TRANSCRIPTION FACTORS, AND A UNIQUE EPIGENETIC LANDSCAPE CONSTITUTE THE EXHAUSTION PROGRAM. RECENTLY, RESEARCHERS HAVE MADE PROGRESS IN UNDERSTANDING EXHAUSTED T CELLS, WITH THE DEFINITION AND IDENTIFICATION OF EXHAUSTED T CELLS CHANGING FROM PHENOTYPE-BASED TO BEING CLASSIFIED AT THE TRANSCRIPTIONAL AND EPIGENETIC LEVELS. RECENT STUDIES HAVE REVEALED THAT EXHAUSTED T CELLS CAN BE SEPARATED INTO TWO SUBGROUPS, NAMELY TCF1(+)PD-1(+) PROGENITOR-LIKE PRECURSOR EXHAUSTED CELLS AND TCF1(-)PD-1(+) TERMINALLY DIFFERENTIATED EXHAUSTED T CELLS. MOREOVER, THE PROGENITOR-LIKE PRECURSOR CELL POPULATION MAY BE A SUBSET OF T CELLS THAT CAN RESPOND TO IMMUNOTHERAPY. STUDIES HAVE ALSO FOUND THAT TOX INITIATES AND DOMINATES THE DEVELOPMENT OF EXHAUSTED T CELLS AT THE TRANSCRIPTIONAL AND EPIGENETIC LEVELS. TOX ALSO MAINTAINS T CELL SURVIVAL AND MAY AFFECT DECISIONS REGARDING TREATMENT STRATEGIES. IN THIS REVIEW, WE DISCUSS THE LATEST DEVELOPMENTS IN T CELL EXHAUSTION IN REGARDS TO DEFINITIONS, SUBPOPULATIONS, DEVELOPMENT MECHANISMS, DIFFERENCES IN DIVERSE DISEASES, AND TREATMENT PROSPECTS FOR EXHAUSTED T CELLS. FURTHERMORE, WE HYPOTHESIZE THAT THE EPIGENETIC STATE REGULATED BY TOX MIGHT BE THE KEY POINT, WHICH CAN DETERMINE THE REVERSIBILITY OF EXHAUSTION AND THE EFFICACY OF IMMUNOTHERAPY. 2020 11 6136 41 THE EPIGENETICS OF MULTIPLE SCLEROSIS AND OTHER RELATED DISORDERS. MULTIPLE SCLEROSIS (MS) IS A DEMYELINATING DISEASE CHARACTERIZED BY CHRONIC INFLAMMATION OF THE CENTRAL NERVOUS SYSTEM (CNS) GRAY AND WHITE MATTER. ALTHOUGH THE CAUSE OF MS IS UNKNOWN, IT IS WIDELY APPRECIATED THAT INNATE AND ADAPTIVE IMMUNE PROCESSES CONTRIBUTE TO ITS PATHOGENESIS. THESE INCLUDE MICROGLIA/MACROPHAGE ACTIVATION, PRO-INFLAMMATORY T-CELL (TH1) RESPONSES AND HUMORAL RESPONSES. ADDITIONALLY, THERE IS EVIDENCE INDICATING THAT MS HAS A NEURODEGENERATIVE COMPONENT SINCE NEURONAL AND AXONAL LOSS OCCURS EVEN IN THE ABSENCE OF OVERT INFLAMMATION. THESE ASPECTS ALSO FORM THE RATIONALE FOR CLINICAL MANAGEMENT OF THE DISEASE. HOWEVER, THE CURRENTLY AVAILABLE THERAPIES TO CONTROL THE DISEASE ARE ONLY PARTIALLY EFFECTIVE AT BEST INDICATING THAT MORE EFFECTIVE THERAPEUTIC SOLUTIONS ARE URGENTLY NEEDED. IT IS APPRECIATED THAT IN THE IMMUNE-DRIVEN AND NEURODEGENERATIVE PROCESSES MS-SPECIFIC DEREGULATION OF GENE EXPRESSIONS AND RESULTING PROTEIN DYSFUNCTION ARE THOUGHT TO PLAY A CENTRAL ROLE. THESE DEVIATIONS IN GENE EXPRESSION PATTERNS CONTRIBUTE TO THE INFLAMMATORY RESPONSE IN THE CNS, AND TO NEURONAL OR AXONAL LOSS. EPIGENETIC MECHANISMS CONTROL TRANSCRIPTION OF MOST, IF NOT ALL GENES, IN NUCLEATED CELLS INCLUDING CELLS OF THE CNS AND IN HAEMATOPOIETIC CELLS. MS-SPECIFIC ALTERATIONS IN EPIGENETIC REGULATION OF GENE EXPRESSION MAY THEREFORE LIE AT THE HEART OF THE DEREGULATION OF GENE EXPRESSION IN MS. AS SUCH, EPIGENETIC MECHANISMS MOST LIKELY PLAY AN IMPORTANT ROLE IN DISEASE PATHOGENESIS. IN THIS REVIEW WE DISCUSS A ROLE FOR MS-SPECIFIC DEREGULATION OF EPIGENETIC FEATURES THAT CONTROL GENE EXPRESSION IN THE CNS AND IN THE PERIPHERY. FURTHERMORE, WE DISCUSS THE APPLICATION OF SMALL MOLECULE INHIBITORS THAT TARGET THE EPIGENETIC MACHINERY TO AMELIORATE DISEASE IN EXPERIMENTAL ANIMAL MODELS, INDICATING THAT SUCH APPROACHES MAY BE APPLICABLE TO MS PATIENTS. 2014 12 6226 20 THE LINK BETWEEN EPIGENETICS, PAIN SENSITIVITY AND CHRONIC PAIN. INCREASING EVIDENCE SUGGESTS AN ASSOCIATION BETWEEN GENE EXPRESSION AND CLINICAL PAIN. EPIGENETIC MODIFICATIONS ARE THE MAIN MODULATORS OF GENE EXPRESSION OR PROTEIN TRANSLATION IN RESPONSE TO ENVIRONMENTAL STIMULI AND PATHOPHYSIOLOGICAL CONDITIONS. PRECLINICAL AND CLINICAL STUDIES INDICATE THAT EPIGENETIC MODIFICATIONS COULD ALSO IMPACT THE DEVELOPMENT OF PAIN, THE TRANSITION FROM ACUTE TO CHRONIC PAIN, AND THE MAINTENANCE HEREOF. 2022 13 5895 19 T CELL EXHAUSTION: AN EPIGENETICALLY IMPRINTED PHENOTYPIC AND FUNCTIONAL MAKEOVER. A RECENT ARTICLE IN CELL DEMONSTRATES THAT THE ABSENCE OF A SINGLE DNA METHYLTRANSFERASE, DNMT3A, PREVENTS CYTOTOXIC T CELLS FROM ACQUIRING THE HYPOFUNCTIONAL OR EXHAUSTED PHENOTYPE TYPICALLY SEEN IN CHRONIC VIRAL INFECTIONS AND TUMORS. UPON ESTABLISHING A CAUSAL RELATIONSHIP BETWEEN EXHAUSTION-ASSOCIATED EPIGENETIC CHANGES AND REDUCED CD8(+) T CELL FUNCTION, THE AUTHORS PROVIDED MECHANISTIC EVIDENCE THAT EXHAUSTION CONSTITUTES A SPECIFIC DIFFERENTIATION PROGRAM. 2017 14 2389 37 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 15 5476 37 RESTORING T CELL TOLERANCE, EXPLORING THE POTENTIAL OF HISTONE DEACETYLASE INHIBITORS FOR THE TREATMENT OF JUVENILE IDIOPATHIC ARTHRITIS. JUVENILE IDIOPATHIC ARTHRITIS (JIA) IS CHARACTERIZED BY A LOSS OF IMMUNE TOLERANCE. HERE, THE BALANCE BETWEEN THE ACTIVITY OF EFFECTOR T (TEFF) CELLS AND REGULATORY T (TREG) CELLS IS DISTURBED RESULTING IN CHRONIC INFLAMMATION IN THE JOINTS. PRESENTLY, THERAPEUTIC STRATEGIES ARE PREDOMINANTLY AIMED AT SUPPRESSING IMMUNE ACTIVATION AND PRO-INFLAMMATORY EFFECTOR MECHANISMS, IGNORING THE OPPORTUNITY TO ALSO PROMOTE TOLERANCE BY BOOSTING THE REGULATORY SIDE OF THE IMMUNE BALANCE. HISTONE DEACETYLASES (HDACS) CAN DEACETYLATE BOTH HISTONE AND NON-HISTONE PROTEINS AND HAVE BEEN DEMONSTRATED TO MODULATE EPIGENETIC REGULATION AS WELL AS CELLULAR SIGNALING IN VARIOUS CELL TYPES. IMPORTANTLY, HDACS ARE POTENT REGULATORS OF BOTH TEFF CELL AND TREG CELL FUNCTION AND CAN THUS BE REGARDED AS ATTRACTIVE THERAPEUTIC TARGETS IN CHRONIC INFLAMMATORY ARTHRITIS. HDAC INHIBITORS (HDACI) HAVE PROVEN THERAPEUTIC POTENTIAL IN THE CANCER FIELD, AND ARE PRESENTLY BEING EXPLORED FOR THEIR POTENTIAL IN THE TREATMENT OF AUTOIMMUNE DISEASES. SPECIFIC HDACI HAVE ALREADY BEEN DEMONSTRATED TO REDUCE THE SECRETION OF PRO-INFLAMMATORY CYTOKINES BY TEFF CELLS, AND PROMOTE TREG NUMBERS AND SUPPRESSIVE CAPACITY IN VITRO AND IN VIVO. IN THIS REVIEW, WE OUTLINE THE ROLE OF THE DIFFERENT CLASSES OF HDACS IN BOTH TEFF CELL AND TREG CELL FUNCTION. FURTHERMORE, WE WILL REVIEW THE EFFECT OF DIFFERENT HDACI ON T CELL TOLERANCE AND EXPLORE THEIR POTENTIAL AS A THERAPEUTIC STRATEGY FOR THE TREATMENT OF OLIGOARTICULAR AND POLYARTICULAR JIA. 2019 16 5248 34 PROGRAMMED CELL DEATH 1-DIRECTED IMMUNOTHERAPY FOR ENHANCING T-CELL FUNCTION. T-CELL EXHAUSTION IS A UNIQUE STATE THAT APPEARS DURING MANY CHRONIC INFECTIONS AND CANCER AND IS CHARACTERIZED BY LOSS OF PROLIFERATIVE CAPACITY AND EFFECTOR FUNCTION. COMPLEX MECHANISMS ARE INVOLVED IN THIS T-CELL DYSFUNCTION BUT AN INHIBITORY RECEPTOR, PD-1, HAS BEEN IDENTIFIED AS A MAJOR REGULATOR OF T-CELL EXHAUSTION. BLOCKADE OF THE PD-1 PATHWAY CAN REINVIGORATE EXHAUSTED T CELLS, RESULTING IN BETTER CONTROL OF CHRONIC INFECTIONS AND CANCER. NOTABLY, RECENT CLINICAL STUDIES HAVE REVEALED THAT PD-1-DIRECTED IMMUNOTHERAPY IS HIGHLY EFFECTIVE IN CANCER PATIENTS, DEMONSTRATING THAT PD-1 IS A PROMISING THERAPEUTIC TARGET IN HUMANS. IN THIS REVIEW, WE SUMMARIZE OUR CURRENT UNDERSTANDING OF THE EPIGENETIC REGULATION OF PD-1 EXPRESSION IN T CELLS AND DISCUSS POTENTIAL COMBINATION THERAPY WITH PD-1 BLOCKADE TOWARD DEVELOPING MORE EFFECTIVE TREATMENT FOR CHRONIC INFECTIONS AND CANCER. 2013 17 4434 25 MOLECULAR DISSECTION OF CD8(+) T-CELL DYSFUNCTION. CHRONIC VIRAL INFECTIONS AND CANCER OFTEN LEAD TO THE EMERGENCE OF DYSFUNCTIONAL OR 'EXHAUSTED' CD8(+) T CELLS, AND THE RESTORATION OF THEIR FUNCTIONS IS CURRENTLY THE FOCUS OF THERAPEUTIC INTERVENTIONS. IN THIS REVIEW, WE DETAIL RECENT ADVANCES IN THE ANNOTATION OF THE GENE MODULES AND THE EPIGENETIC LANDSCAPE ASSOCIATED WITH T-CELL DYSFUNCTION. TOGETHER WITH ANALYSIS OF SINGLE-CELL TRANSCRIPTOMES, THESE FINDINGS HAVE ENABLED A DEEPER AND MORE PRECISE UNDERSTANDING OF THE TRANSCRIPTIONAL MECHANISMS THAT INDUCE AND MAINTAIN THE DYSFUNCTIONAL STATE AND HIGHLIGHT THE HETEROGENEITY OF CD8(+) T-CELL PHENOTYPES PRESENT IN CHRONICALLY INFLAMED TISSUE. WE DISCUSS THE RELEVANCE OF THESE FINDINGS FOR UNDERSTANDING THE TRANSCRIPTIONAL AND SPATIAL REGULATION OF DYSFUNCTIONAL T CELLS AND FOR THE DESIGN OF THERAPEUTICS. 2017 18 6496 50 TRAINED IMMUNITY CONTRIBUTION TO AUTOIMMUNE AND INFLAMMATORY DISORDERS. A DYSREGULATED IMMUNE RESPONSE TOWARD SELF-ANTIGENS CHARACTERIZES AUTOIMMUNE AND AUTOINFLAMMATORY (AIF) DISORDERS. AUTOANTIBODIES OR AUTOREACTIVE T CELLS CONTRIBUTE TO AUTOIMMUNE DISEASES, WHILE AUTOINFLAMMATION RESULTS FROM A HYPER-FUNCTIONAL INNATE IMMUNE SYSTEM. ASIDE FROM THEIR DIFFERENCES, MANY STUDIES SUGGEST THAT MONOCYTES AND MACROPHAGES (MO/MA) SIGNIFICANTLY CONTRIBUTE TO THE DEVELOPMENT OF BOTH TYPES OF DISEASE. MO/MA ARE INNATE IMMUNE CELLS THAT PROMOTE AN IMMUNE-MODULATORY, PRO-INFLAMMATORY, OR REPAIR RESPONSE DEPENDING ON THE MICROENVIRONMENT. HOWEVER, UNDERSTANDING THE CONTRIBUTION OF THESE CELLS TO DIFFERENT IMMUNE DISORDERS HAS BEEN DIFFICULT DUE TO THEIR HIGH FUNCTIONAL AND PHENOTYPIC PLASTICITY. SEVERAL FACTORS CAN INFLUENCE THE FUNCTION OF MO/MA UNDER THE LANDSCAPE OF AUTOIMMUNE/AUTOINFLAMMATORY DISEASES, SUCH AS GENETIC PREDISPOSITION, EPIGENETIC CHANGES, OR INFECTIONS. FOR INSTANCE, SOME VACCINES AND MICROORGANISMS CAN INDUCE EPIGENETIC CHANGES IN MO/MA, MODIFYING THEIR FUNCTIONAL RESPONSES. THIS PHENOMENON IS KNOWN AS TRAINED IMMUNITY. TRAINED IMMUNITY CAN BE MEDIATED BY MO/MA AND NK CELLS INDEPENDENTLY OF T AND B CELL FUNCTION. IT IS DEFINED AS THE ALTERED INNATE IMMUNE RESPONSE TO THE SAME OR DIFFERENT MICROORGANISMS DURING A SECOND ENCOUNTER. THE IMPROVEMENT IN CELL FUNCTION IS RELATED TO EPIGENETIC AND METABOLIC CHANGES THAT MODIFY GENE EXPRESSION. ALTHOUGH THE BENEFITS OF IMMUNE TRAINING HAVE BEEN HIGHLIGHTED IN A VACCINATION CONTEXT, THE EFFECTS OF THIS TYPE OF IMMUNE RESPONSE ON AUTOIMMUNITY AND CHRONIC INFLAMMATION STILL REMAIN CONTROVERSIAL. INDUCTION OF TRAINED IMMUNITY REPROGRAMS CELLULAR METABOLISM IN HEMATOPOIETIC STEM CELLS (HSCS), TRANSMITTING A MEMORY-LIKE PHENOTYPE TO THE CELLS. THUS, TRAINED MO/MA DERIVED FROM HSCS TYPICALLY PRESENT A METABOLIC SHIFT TOWARD GLYCOLYSIS, WHICH LEADS TO THE MODIFICATION OF THE CHROMATIN ARCHITECTURE. DURING TRAINED IMMUNITY, THE EPIGENETIC CHANGES FACILITATE THE SPECIFIC GENE EXPRESSION AFTER SECONDARY CHALLENGE WITH OTHER STIMULI. CONSEQUENTLY, THE ENHANCED PRO-INFLAMMATORY RESPONSE COULD CONTRIBUTE TO DEVELOPING OR MAINTAINING AUTOIMMUNE/AUTOINFLAMMATORY DISEASES. HOWEVER, THE PREDICTION OF THE OUTCOME IS NOT SIMPLE, AND OTHER STUDIES PROPOSE THAT TRAINED IMMUNITY CAN INDUCE A BENEFICIAL RESPONSE BOTH IN AIF AND AUTOIMMUNE CONDITIONS BY INDUCING ANTI-INFLAMMATORY RESPONSES. THIS ARTICLE DESCRIBES THE METABOLIC AND EPIGENETIC MECHANISMS INVOLVED IN TRAINED IMMUNITY THAT AFFECT MO/MA, CONTRAPOSING THE CONTROVERSIAL EVIDENCE ON HOW IT MAY IMPACT AUTOIMMUNE/AUTOINFLAMMATION CONDITIONS. 2022 19 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 20 6677 41 USING EPIGENETICS TO DEFINE VACCINE-INDUCED MEMORY T CELLS. MEMORY T CELLS GENERATED FROM ACUTE INFECTION OR VACCINATION HAVE THE POTENTIAL TO PROVIDE THE HOST WITH LIFE-LONG IMMUNITY AGAINST RE-INFECTION. PROTECTION BY MEMORY T CELLS IS ACHIEVED THROUGH THEIR ACQUIRED ABILITY TO PERSIST AT ANATOMICAL SITES OF THE PRIMARY INFECTION AS WELL AS MAINTAINING A HEIGHTENED ABILITY TO RECALL EFFECTOR FUNCTIONS. THE MAINTENANCE OF CD8 AND CD4 T CELL FUNCTION IN A STATE OF READINESS IS KEY TO LIFE-LONG IMMUNITY AND MANIFEST THROUGH CHANGES IN TRANSCRIPTIONAL REGULATION. YET, THE ABILITY TO IDENTIFY POISED TRANSCRIPTIONAL PROGRAMS AT THE MAINTENANCE STAGE OF THE RESPONSE IS LACKING FROM MOST TRANSCRIPTIONAL PROFILING STUDIES OF MEMORY T CELLS. EPIGENETIC PROFILING ALLOWS FOR THE ASSESSMENT OF TRANSCRIPTIONALLY POISED (PROMOTERS THAT ARE READILY ACCESSIBLE FOR TRANSCRIPTION) STATES OF ANTIGEN-SPECIFIC T CELLS WITHOUT MANIPULATION OF THE ACTIVATION STATE OF THE CELL. HERE WE REVIEW RECENT STUDIES THAT HAVE EXAMINED EPIGENETIC PROGRAMS OF EFFECTOR AND MEMORY T CELL SUBSETS. THESE REPORTS DEMONSTRATE THAT ACQUISITION OF EPIGENETIC PROGRAMS DURING MEMORY T CELL DIFFERENTIATION TO ACUTE AND CHRONIC INFECTIONS IS COUPLED TO, AND POTENTIALLY REGULATE, THE CELL'S RECALL RESPONSE. WE DISCUSS THE USEFULNESS OF EPIGENETIC PROFILING IN CHARACTERIZING T CELL DIFFERENTIATION STATE AND FUNCTION FOR PRECLINICAL EVALUATION OF VACCINES AND THE CURRENT METHODOLOGIES FOR SINGLE LOCUS VERSUS GENOME-WIDE EPIGENETIC PROFILING. 2013