1 5431 109 REGULATORY T CELLS: PATHOPHYSIOLOGICAL ROLES AND CLINICAL APPLICATIONS. INFLAMMATION AND IMMUNE RESPONSES AFTER TISSUE INJURY PLAY PIVOTAL ROLES IN THE RESOLUTION OF INFLAMMATION, TISSUE RECOVERY, FIBROSIS, AND REMODELING. REGULATORY T CELLS (TREGS) ARE RESPONSIBLE FOR IMMUNE TOLERANCE AND ARE USUALLY ACTIVATED IN SECONDARY LYMPHATIC TISSUES. ACTIVATED TREGS SUBSEQUENTLY REGULATE EFFECTOR T CELL AND DENDRITIC CELL ACTIVATION. FOR CLINICAL APPLICATIONS SUCH AS THE SUPPRESSION OF BOTH AUTOIMMUNE DISEASES AND THE REJECTION OF TRANSPLANTED ORGANS, METHODS TO GENERATE STABILIZED ANTIGEN-SPECIFIC TREGS ARE REQUIRED. FOR THIS PURPOSE, TRANSCRIPTIONAL AND EPIGENETIC REGULATION OF FOXP3 EXPRESSION HAS BEEN INVESTIGATED. IN ADDITION TO CONVENTIONAL TREGS, THERE ARE SOME TREGS THAT RESIDE IN TISSUES AND ARE CALLED TISSUE TREGS. TISSUE TREGS EXHIBIT TISSUE-SPECIFIC FUNCTIONS THAT CONTRIBUTE TO THE MAINTENANCE OF TISSUE HOMEOSTASIS AND REPAIR. SUCH TISSUE TREGS COULD ALSO BE USEFUL FOR TREG-BASED CELL THERAPY. WE RECENTLY DISCOVERED BRAIN TREGS THAT ACCUMULATE IN THE BRAIN DURING THE CHRONIC PHASE OF ISCHEMIC BRAIN INJURY. BRAIN TREGS RESEMBLE OTHER TISSUE TREGS, BUT ARE UNIQUE IN EXPRESSING NEURAL CELL-SPECIFIC GENES SUCH AS THE SEROTONIN RECEPTOR (HTR7); CONSEQUENTLY, BRAIN TREGS RESPOND TO SEROTONIN. HERE, WE DESCRIBE OUR EXPERIENCES IN THE USE OF TREGS TO SUPPRESS GRAFT-VERSUS-HOST DISEASE AND TO PROMOTE NEURAL RECOVERY AFTER STROKE. 2020 2 4200 41 METABOLIC REQUIREMENTS OF TH17 CELLS AND OF B CELLS: REGULATION AND DEFECTS IN HEALTH AND IN INFLAMMATORY DISEASES. THE IMMUNE SYSTEM PROTECTS FROM INFECTIONS AND CANCER THROUGH COMPLEX CELLULAR NETWORKS. FOR THIS PURPOSE, IMMUNE CELLS REQUIRE WELL-DEVELOPED MECHANISMS OF ENERGY GENERATION. HOWEVER, THE IMMUNE SYSTEM ITSELF CAN ALSO CAUSE DISEASES WHEN DEFECTIVE REGULATION RESULTS IN THE EMERGENCE OF AUTOREACTIVE LYMPHOCYTES. RECENT STUDIES PROVIDE INSIGHTS INTO HOW DIFFERENTIAL PATTERNS OF IMMUNE CELL RESPONSES ARE ASSOCIATED WITH SELECTIVE METABOLIC PATHWAYS. THIS REVIEW WILL EXAMINE THE CHANGING METABOLIC REQUIREMENTS OF TH17 CELLS AND OF B CELLS AT DIFFERENT STAGES OF THEIR DEVELOPMENT AND ACTIVATION. BOTH CELLS PROVIDE PROTECTION BUT CAN ALSO MEDIATE DISEASES THROUGH THE PRODUCTION OF AUTOANTIBODIES AND THE PRODUCTION OF PROINFLAMMATORY MEDIATORS. IN HEALTH, B CELLS PRODUCE ANTIBODIES AND CYTOKINES AND PRESENT ANTIGENS TO T CELLS TO MOUNT SPECIFIC IMMUNITY. TH17 CELLS, ON THE OTHER HAND, PROVIDE PROTECTION AGAINST EXTRA CELLULAR PATHOGENS AT MUCOSAL SURFACES BUT CAN ALSO DRIVE CHRONIC INFLAMMATION. THE LATTER CELLS CAN ALSO PROMOTE THE DIFFERENTIATION OF B CELLS TO PLASMA CELLS TO PRODUCE MORE AUTOANTIBODIES. METABOLISM-REGULATED CHECKPOINTS AT DIFFERENT STAGES OF THEIR DEVELOPMENT ENSURE THE THAT SELF-REACTIVE B CELLS CLONES AND NEEDLESS PRODUCTION OF INTERLEUKIN (IL-)17 ARE LIMITED. THE METABOLIC REGULATION OF THE TWO CELL TYPES HAS SOME SIMILARITIES, E.G. THE UTILITY OF HYPOXIA INDUCED FACTOR (HIF)1ALPHA DURING LOW OXYGEN TENSION, TO PREVENT AUTOIMMUNITY AND REGULATE INFLAMMATION. THERE ARE ALSO CLEAR DIFFERENCES, AS TH17 CELLS ONLY ARE VULNERABLE TO THE LACK OF CERTAIN AMINO ACIDS. B CELLS, UNLIKE TH17 CELLS, ARE ALSO DEPENDENT OF MECHANISTIC TARGET OF RAPAMYCIN 2 (MTORC2) TO FUNCTION. SIGNIFICANT KNOWLEDGE HAS RECENTLY BEEN GAINED, PARTICULARLY ON TH17 CELLS, ON HOW METABOLISM REGULATES THESE CELLS THROUGH INFLUENCING THEIR EPIGENOME. METABOLIC DYSREGULATION OF TH17 CELLS AND B CELLS CAN LEAD TO CHRONIC INFLAMMATION. DISEASE ASSOCIATED ALTERATIONS IN THE GENOME CAN, IN ADDITION, CAUSE DYSREGULATION TO METABOLISM AND, THEREBY, RESULT IN EPIGENETIC ALTERATIONS IN THESE CELLS. RECENT STUDIES HIGHLIGHT HOW PATHOLOGY CAN RESULT FROM THE COOPERATION BETWEEN THE TWO CELL TYPES BUT ONLY FEW HAVE SO FAR ADDRESSED THE KEY METABOLIC ALTERATIONS IN SUCH SETTINGS. KNOWLEDGE OF THE IMPACT OF METABOLIC DYSFUNCTION ON CHRONIC INFLAMMATION AND PATHOLOGY CAN REVEAL NOVEL THERAPEUTIC TARGETS TO TREAT SUCH DISEASES. 2022 3 6535 27 TRANSCRIPTIONAL REGULATION OF THE ANTI-INFLAMMATORY CYTOKINE IL-10 IN ACQUIRED IMMUNE CELLS. ALTHOUGH THE MAJOR ROLE OF THE IMMUNE RESPONSE IS HOST DEFENSE FROM A WIDE RANGE OF POTENTIALLY PATHOGENIC MICROORGANISMS, EXCESS IMMUNE RESPONSES CAN RESULT IN SEVERE HOST DAMAGE. THE HOST THUS REQUIRES ANTI-INFLAMMATORY MECHANISMS TO PREVENT REACTIVITY TO SELF. INTERLEUKIN-10 (IL-10) IS A CYTOKINE WITH BROAD ANTI-INFLAMMATORY PROPERTIES INVOLVED IN THE PATHOGENESIS OF VARIOUS DISEASES. IL-10 WAS ORIGINALLY DESCRIBED AS A T HELPER (T(H)2) DERIVED CYTOKINE, BUT FURTHER STUDIES INDICATED THAT IL-10 IS EXPRESSED NOT ONLY BY MANY CELLS OF THE ADAPTIVE IMMUNE SYSTEM, INCLUDING T AND B CELLS, BUT ALSO BY THE INNATE IMMUNE CELLS, INCLUDING DENDRITIC CELLS (DCS), MACROPHAGES, MAST CELLS, AND NATURAL KILLER (NK) CELLS. IN ADDITION, IL-10 CAN BE INDUCED IN T(H)1 AND T(H)17 CELLS BY CHRONIC INFLAMMATION AS A SYSTEM OF FEEDBACK REGULATION. IN THIS REVIEW, WE FOCUS ON THE MOLECULAR MECHANISMS UNDERLYING IL10 GENE EXPRESSION IN ADAPTIVE IMMUNE CELLS AND SUMMARIZE THE RECENT PROGRESSES IN EPIGENETIC AND TRANSCRIPTIONAL REGULATION OF THE IL10 GENE. UNDERSTANDING THE TRANSCRIPTIONAL REGULATORY EVENTS MAY HELP IN THE DEVELOPMENT OF NEW STRATEGIES TO CONTROL INFLAMMATORY DISEASES. 2012 4 5415 28 REGULATION OF CELLULAR IMMUNE RESPONSES IN SEPSIS BY HISTONE MODIFICATIONS. SEVERE SEPSIS, SEPTIC SHOCK, AND RELATED INFLAMMATORY SYNDROMES ARE DRIVEN BY THE ABERRANT EXPRESSION OF PROINFLAMMATORY MEDIATORS BY IMMUNE CELLS. DURING THE ACUTE PHASE OF SEPSIS, OVEREXPRESSION OF CHEMOKINES AND CYTOKINES DRIVES PHYSIOLOGICAL STRESS LEADING TO ORGAN FAILURE AND MORTALITY. FOLLOWING RECOVERY FROM SEPSIS, THE IMMUNE SYSTEM EXHIBITS PROFOUND IMMUNOSUPPRESSION, EVIDENCED BY AN INABILITY TO PRODUCE THE SAME PROINFLAMMATORY MEDIATORS THAT ARE REQUIRED FOR NORMAL RESPONSES TO INFECTIOUS MICROORGANISMS. GENE EXPRESSION IN INFLAMMATORY RESPONSES IS INFLUENCED BY THE TRANSCRIPTIONAL ACCESSIBILITY OF THE CHROMATIN, WITH HISTONE POSTTRANSLATIONAL MODIFICATIONS DETERMINING WHETHER INFLAMMATORY GENE LOCI ARE SET TO TRANSCRIPTIONALLY ACTIVE, REPRESSED, OR POISED STATES. EXPERIMENTAL EVIDENCE INDICATES THAT HISTONE MODIFICATIONS PLAY A CENTRAL ROLE IN GOVERNING THE CYTOKINE STORM OF SEVERE SEPSIS, AND THAT ABERRANT CHROMATIN MODIFICATIONS INDUCED DURING THE ACUTE PHASE OF SEPSIS MAY MEDIATE CHRONIC IMMUNOSUPPRESSION IN SEPSIS SURVIVORS. THIS REVIEW WILL FOCUS ON THE ROLE OF HISTONE MODIFICATIONS IN GOVERNING IMMUNE RESPONSES IN SEVERE SEPSIS, WITH AN EMPHASIS ON SPECIFIC LEUKOCYTE SUBSETS AND THE HISTONE MODIFICATIONS OBSERVED IN THESE CELLS DURING CHRONIC STAGES OF SEPSIS. ADDITIONALLY, THE EXPRESSION AND FUNCTION OF CHROMATIN-MODIFYING ENZYMES (CMES) WILL BE DISCUSSED IN THE CONTEXT OF SEVERE SEPSIS, AS POTENTIAL MEDIATORS OF EPIGENETIC REGULATION OF GENE EXPRESSION IN SEPSIS RESPONSES. IN SUMMARY, THIS REVIEW WILL ARGUE FOR THE USE OF CHROMATIN MODIFICATIONS AND CME EXPRESSION IN LEUKOCYTES AS POTENTIAL BIOMARKERS OF IMMUNOSUPPRESSION IN PATIENTS WITH SEVERE SEPSIS. 2017 5 1876 35 EMERGING ROLES FOR EPIGENETIC PROGRAMMING IN THE CONTROL OF INFLAMMATORY SIGNALING INTEGRATION IN HEATH AND DISEASE. MACROPHAGES AND DENDRITIC CELLS INITIATE THE INNATE IMMUNE RESPONSE TO INFECTION AND INJURY AND CONTRIBUTE TO INFLAMMATORY SIGNALING TO MAINTAIN THE HOMEOSTASIS OF VARIOUS TISSUES, WHICH INCLUDES RESIDENT MACROPHAGES FOR THE ELIMINATION OF INVADING MICROORGANISMS AND TISSUE DAMAGE. INAPPROPRIATE INFLAMMATORY SIGNALING CAN LEAD TO PERSISTENT INFLAMMATION AND FURTHER DEVELOP INTO AUTOIMMUNE AND INFLAMMATION-ASSOCIATED DISEASES. INFLAMMATORY SIGNALING PATHWAYS HAVE BEEN WELL CHARACTERIZED, BUT HOW THESE SIGNALING PATHWAYS ARE CONVERTED INTO SUSTAINED AND DIVERSE PATTERNS OF EXPRESSION OF CYTOKINES, CHEMOKINES, AND OTHER GENES IN RESPONSE TO ENVIRONMENTAL CHALLENGES IS UNCLEAR. EMERGING EVIDENCE SUGGESTS THE IMPORTANT ROLE OF EPIGENETIC MECHANISMS IN FINELY TUNING THE OUTCOME OF THE HOST INNATE IMMUNE RESPONSE. AN UNDERSTANDING OF EPIGENETIC REGULATION OF INNATE IMMUNE CELL IDENTITY AND FUNCTION WILL ENABLE THE IDENTIFICATION OF THE MECHANISM BETWEEN GENE-SPECIFIC HOST DEFENSES AND INFLAMMATORY DISEASE AND WILL ALSO ALLOW FOR EXPLORATION OF THE PROGRAM OF INNATE IMMUNE MEMORY IN HEALTH AND DISEASE. THIS INFORMATION COULD BE USED TO DEVELOP THERAPEUTIC AGENTS TO ENHANCE THE HOST RESPONSE, PREVENTING CHRONIC INFLAMMATION THROUGH PRESERVING TISSUES AND SIGNALING INTEGRITY. 2017 6 3703 24 INFLAMMATORY SIGNALLING AS MEDIATOR OF EPIGENETIC MODULATION IN TISSUE-SPECIFIC CHRONIC INFLAMMATION. RECENT SUCCESSES OF THERAPEUTIC INTERVENTION IN CHRONIC INFLAMMATORY DISEASES USING EPIGENETIC MODIFIERS SUCH AS HISTONE DEACETYLASE INHIBITORS AND INHIBITORS OF DNA METHYLATION SUGGEST THAT EPIGENETIC REPROGRAMMING PLAYS A ROLE IN THE AETIOLOGY OF THESE DISEASES. THE EPIGENETIC SIGNATURE OF A GIVEN IMMUNE CELL IS REFLECTED IN THE HISTORY OF MODIFICATIONS FROM DIFFERENT SIGNALS THE CELL HAS BEEN SUBJECTED TO DURING DIFFERENTIATION. LIKE OTHER CELLS, DIFFERENTIATING IMMUNE CELLS ARE DEPENDENT ON A COMPLEX COMBINATION OF INTER- AND INTRACELL SIGNALLING AS WELL AS TRANSCRIPTION MACHINERIES TO MODULATE THEIR EPIGENOMES IN ORDER TO MEDIATE DIFFERENTIATION. DESPITE EXTENSIVE RESEARCH INTO THESE PROCESSES, THE LINK BETWEEN CELLULAR SIGNALLING AND EPIGENETIC MODULATION REMAINS POORLY UNDERSTOOD. HERE, WE REVIEW RECENT PROGRESS AND DISCUSS KEY FACTORS DRIVING EPIGENETIC MODULATION IN CHRONIC INFLAMMATION. 2009 7 2344 24 EPIGENETIC REGULATION OF MACROPHAGES: FROM HOMEOSTASIS MAINTENANCE TO HOST DEFENSE. MACROPHAGES ARE CRUCIAL MEMBERS OF THE INNATE IMMUNE RESPONSE AND IMPORTANT REGULATORS. THE DIFFERENTIATION AND ACTIVATION OF MACROPHAGES REQUIRE THE TIMELY REGULATION OF GENE EXPRESSION, WHICH DEPENDS ON THE INTERACTION OF A VARIETY OF FACTORS, INCLUDING TRANSCRIPTION FACTORS AND EPIGENETIC MODIFICATIONS. EPIGENETIC CHANGES ALSO GIVE MACROPHAGES THE ABILITY TO SWITCH RAPIDLY BETWEEN CELLULAR PROGRAMS, INDICATING THE ABILITY OF EPIGENETIC MECHANISMS TO AFFECT PHENOTYPE PLASTICITY. IN THIS REVIEW, WE FOCUS ON KEY EPIGENETIC EVENTS ASSOCIATED WITH MACROPHAGE FATE, HIGHLIGHTING EVENTS RELATED TO THE MAINTENANCE OF TISSUE HOMEOSTASIS, RESPONSES TO DIFFERENT STIMULI AND THE FORMATION OF INNATE IMMUNE MEMORY. FURTHER UNDERSTANDING OF THE EPIGENETIC REGULATION OF MACROPHAGES WILL BE HELPFUL FOR MAINTAINING TISSUE INTEGRITY, PREVENTING CHRONIC INFLAMMATORY DISEASES AND DEVELOPING THERAPIES TO ENHANCE HOST DEFENSE. 2020 8 6677 26 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 9 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 10 4967 37 PATHOLOGICAL CONDITIONS RE-SHAPE PHYSIOLOGICAL TREGS INTO PATHOLOGICAL TREGS. CD4(+)FOXP3(+) REGULATORY T CELLS (TREGS) ARE A SUBSET OF CD4 T CELLS THAT PLAY AN ESSENTIAL ROLE IN MAINTAINING PERIPHERAL IMMUNE TOLERANCE, CONTROLLING ACUTE AND CHRONIC INFLAMMATION, ALLERGY, AUTOIMMUNE DISEASES, AND ANTI-CANCER IMMUNE RESPONSES. OVER THE PAST 20 YEARS, SIGNIFICANT PROGRESS HAS BEEN MADE SINCE TREGS WERE FIRST CHARACTERIZED IN 1995. MANY CONCEPTS AND PRINCIPLES REGARDING TREGS GENERATION, PHENOTYPIC FEATURES, SUBSETS (TTREGS, PTREGS, ITREGS, AND ITREG35), TISSUE SPECIFICITY (CENTRAL TREGS, EFFECTOR TREGS, AND TISSUE RESIDENT TREGS), HOMEOSTASIS (HIGHLY DYNAMIC AND APOPTOTIC), REGULATION OF TREGS BY RECEPTORS FOR PAMPS AND DAMPS, TREG PLASTICITY (RE-DIFFERENTIATION TO OTHER CD4 T HELPER CELL SUBSETS, TH1, TH2, TFH AND TH17), AND EPIGENETIC REGULATION OF TREGS PHENOTYPES AND FUNCTIONS HAVE BEEN INNOVATED. IN THIS CONCISE REVIEW, WE WANT TO BRIEFLY ANALYZE THESE EIGHT NEW PROGRESSES IN THE STUDY OF TREGS. WE HAVE ALSO PROPOSED FOR THE FIRST TIME A NOVEL CONCEPT THAT "PHYSIOLOGICAL TREGS" HAVE BEEN RE-SHAPED INTO "PATHOLOGICAL TREGS" IN VARIOUS PATHOLOGICAL ENVIRONMENTS. CONTINUING OF THE IMPROVEMENT IN OUR UNDERSTANDING ON THIS IMPORTANT CELLULAR COMPONENT ABOUT THE IMMUNE TOLERANCE AND IMMUNE SUPPRESSION, WOULD LEAD TO THE FUTURE DEVELOPMENT OF NOVEL THERAPEUTICS APPROACHES FOR ACUTE AND CHRONIC INFLAMMATORY DISEASES, ALLERGY, ALLOGENEIC TRANSPLANTATION-RELATED IMMUNITY, SEPSIS, AUTOIMMUNE DISEASES, AND CANCERS. 2015 11 5900 29 T-CELL EXHAUSTION IN ORGAN TRANSPLANTATION. EXHAUSTION OF T CELLS OCCURS IN RESPONSE TO LONG-TERM EXPOSURE TO SELF AND FOREIGN ANTIGENS. IT LIMITS T CELL CAPACITY TO PROLIFERATE AND PRODUCE CYTOKINES, LEADING TO AN IMPAIRED ABILITY TO CLEAR CHRONIC INFECTIONS OR ERADICATE TUMORS. T-CELL EXHAUSTION IS ASSOCIATED WITH A SPECIFIC TRANSCRIPTIONAL, EPIGENETIC, AND METABOLIC PROGRAM AND CHARACTERISTIC CELL SURFACE MARKERS' EXPRESSION. RECENT STUDIES HAVE BEGUN TO ELUCIDATE THE ROLE OF T-CELL EXHAUSTION IN TRANSPLANT. HIGHER LEVELS OF EXHAUSTED T CELLS HAVE BEEN ASSOCIATED WITH BETTER GRAFT FUNCTION IN KIDNEY TRANSPLANT RECIPIENTS. IN CONTRAST, REINVIGORATING EXHAUSTED T CELLS BY IMMUNE CHECKPOINT BLOCKADE THERAPIES, WHILE PROMOTING TUMOR CLEARANCE, INCREASES THE RISK OF ACUTE REJECTION. LYMPHOCYTE DEPLETION AND HIGH ALLOANTIGEN LOAD HAVE BEEN IDENTIFIED AS MAJOR DRIVERS OF T-CELL EXHAUSTION. THIS COULD ACCOUNT, AT LEAST IN PART, FOR THE REDUCED RATES OF ACUTE REJECTION IN ORGAN TRANSPLANT RECIPIENTS INDUCED WITH THYMOGLOBULIN AND FOR THE PRO-TOLEROGENIC EFFECTS OF A LARGE ORGAN SUCH AS THE LIVER. AMONG THE DRUGS THAT ARE WIDELY USED FOR MAINTENANCE IMMUNOSUPPRESSION, CALCINEURIN INHIBITORS HAVE A CONTRASTING INHIBITORY EFFECT ON EXHAUSTION OF T CELLS, WHILE THE INFLUENCE OF MTOR INHIBITORS IS STILL UNCLEAR. HARNESSING OR ENCOURAGING THE NATURAL PROCESSES OF EXHAUSTION MAY PROVIDE A NOVEL STRATEGY TO PROMOTE GRAFT SURVIVAL AND TRANSPLANTATION TOLERANCE. 2022 12 233 21 ADAPTIVE T CELL TUNING IN IMMUNE REGULATION AND IMMUNOTHERAPY OF AUTOIMMUNE DISEASES(?). LYMPHOCYTE RECEPTORS CONFER ANTIGEN SPECIFICITY ON THE ADAPTIVE IMMUNE RESPONSE. INCREASING EVIDENCE POINTS TO THE ROLE OF ADAPTIVE TUNING PARTICULARLY AMONGST CD4(+) T CELL RESPONSES. THIS REVIEW SUMMARISES HOW T CELL TUNING IMPACTS ON CRITICALLY IMPORTANT ASPECTS OF IMMUNE REGULATION INCLUDING THYMIC SELECTION, THE IMMUNE RESPONSE TO CHRONIC ANTIGEN EXPOSURE AND ANTIGEN-SPECIFIC IMMUNOTHERAPY OF AUTOIMMUNE CONDITIONS. RECENT WORK HAS REVEALED A NOVEL MECHANISM FOR T CELL ANERGY AND REGULATORY TYPE 1 T CELL DIFFERENTIATION THROUGH A LIMITATION OF T CELL RECEPTOR MEDIATED SIGNALLING COMBINED WITH EPIGENETIC PRIMING OF TOLERANCE ASSOCIATED GENES. 2022 13 2070 20 EPIGENETIC CONTROL OF SKIN IMMUNITY. EPIGENETICS HAS BEEN WELL UNDERSTOOD FOR ITS ROLE IN CELL DEVELOPMENT; HOWEVER, IT IS NOW KNOWN TO REGULATE MANY PROCESSES INVOLVED IN IMMUNE CELL ACTIVATION IN A VARIETY OF CELLS. THE SKIN MAINTAINS HOMEOSTASIS VIA CROSSTALK BETWEEN IMMUNE AND NON-IMMUNE CELLS. DISRUPTION OF NORMAL EPIGENETIC REGULATION IN THESE CELLS MAY ALTER THE TRANSCRIPTION OF IMMUNE-REGULATORY FACTORS AND AFFECT THE IMMUNOLOGICAL BALANCE IN THE SKIN. THIS REVIEW SUMMARIZES RECENT EVIDENCE FOR THE EPIGENETIC REGULATION OF SKIN IMMUNITY. MUCH OF WHAT IS KNOWN ABOUT EPIGENETIC INVOLVEMENT IN SKIN IMMUNITY IS ASSOCIATED WITH DNA METHYLATION. THIS REVIEW FOCUSES ON EPIGENETIC REGULATION OF HISTONE MODIFICATION AND CHROMATIN REMODELING AND DESCRIBES THEIR ROLE IN THE TRANSCRIPTIONAL REGULATION OF IMMUNE-REGULATORY FACTORS. WHILE MUCH IS STILL UNKNOWN REGARDING THE REGULATION OF SKIN IMMUNITY VIA HISTONE MODIFICATION OR CHROMATIN REMODELING, THESE PROCESSES MAY UNDERLIE THE PATHOGENESIS OF CHRONIC CUTANEOUS IMMUNE DISORDERS. 2023 14 4439 26 MOLECULAR GENETIC AND EPIGENETIC BASIS OF MULTIPLE SCLEROSIS. MULTIPLE SCLEROSIS (MS) IS A CHRONIC IMMUNE-MEDIATED DISEASE OF SPINAL CORD AND BRAIN. THE INITIAL EVENT IN MS OCCURS WHEN ACTIVATED CD4(+) T CELLS IN PERIPHERY EXACERBATES IMMUNE RESPONSES BY STIMULATING IMMUNE CELLS SUCH AS B CELLS, CD8(+) CELLS, MAST CELLS, GRANULOCYTES AND MONOCYTES. THESE PROINFLAMMATORY CELLS PASS BLOOD BRAIN BARRIER BY SECRETING PROINFLAMMATORY CYTOKINES INCLUDING TNF-ALPHA AND INF-(GAMMA) WHICH ACTIVATE ADHESION FACTORS. APCS (ANTIGEN-PRESENTING CELLS) REACTIVATE CD4(+) T CELLS AFTER INFILTRATING THE CNS AND CD4(+) T CELLS PRODUCE CYTOKINES AND CHEMOKINES. THESE PROINFLAMMATORY CYTOKINES AGGRAVATE INFLAMMATION BY INDUCING MYELIN PHAGOCYTOSIS THROUGH MICROGLIA AND ASTROCYTES ACTIVATION. MS IS BELIEVED TO HAVE A MULTIFACTORIAL ORIGIN THAT INCLUDES A COMBINATION OF MULTIPLE GENETIC, ENVIRONMENTAL AND STOCHASTIC FACTORS. ALTHOUGH THE EXACT COMPONENT OF MS RISKS THAT CAN BE EXPLAINED BY THESE FACTORS IS DIFFICULT TO DETERMINE, ESTIMATES BASED ON GENETIC AND EPIDEMIOLOGICAL STUDIES SUGGEST THAT UP TO 60-70 % OF THE TOTAL RISK OF MS MAY BE CONTRIBUTE TO GENETIC FACTORS. IN CONTINUE, FIRSTLY WE PROVIDE AN OVERVIEW OF THE CURRENT UNDERSTANDING OF EPIGENETIC MECHANISMS, AND SO PRESENT EVIDENCE OF HOW THE EPIGENETIC MODIFICATIONS CONTRIBUTE TO INCREASED SUSCEPTIBILITY OF MS. WE ALSO EXPLAIN HOW SPECIFIED EPIGENETIC MODIFICATIONS MAY INFLUENCE THE PATHOPHYSIOLOGY AND KEY ASPECTS OF DISEASE IN MS (DEMYELINATION, REMYELINATION, INFLAMMATION, AND NEURODEGENERATION). FINALLY, WE TEND TO DISCUSS HOW ENVIRONMENTAL FACTORS AND EPIGENETIC MECHANISMS MAY INTERACT TO HAVE AN EFFECT ON MS RISK AND CLINICAL OUTCOME AND RECOMMEND NEW THERAPEUTIC INTERVENTIONS THAT MIGHT MODULATE PATIENTS' EPIGENETIC PROFILES. 2017 15 127 29 A TRANSCRIPTIONAL PERSPECTIVE ON HUMAN MACROPHAGE BIOLOGY. MACROPHAGES ARE A MAJOR CELL TYPE IN TISSUE HOMEOSTASIS AND CONTRIBUTE TO BOTH PATHOLOGY AND RESOLUTION IN ALL ACUTE AND CHRONIC INFLAMMATORY DISEASES RANGING FROM INFECTIONS, CANCER, OBESITY, ATHEROSCLEROSIS, AUTOIMMUNE DISORDERS TO NEURODEGENERATIVE DISEASES SUCH AS ALZHEIMER'S DISEASE. THE CELLULAR AND FUNCTIONAL DIVERSITY OF MACROPHAGES DEPENDS UPON TIGHTLY REGULATED TRANSCRIPTION. THE INNATE IMMUNE SYSTEM IS UNDER PROFOUND EVOLUTIONARY SELECTION. THERE IS INCREASING RECOGNITION THAT HUMAN MACROPHAGE BIOLOGY DIFFERS VERY SIGNIFICANTLY FROM THAT OF COMMONLY STUDIED ANIMAL MODELS, WHICH THEREFORE CAN HAVE A LIMITED PREDICTIVE VALUE. HERE WE REPORT ON THE NEWEST FINDINGS ON TRANSCRIPTIONAL CONTROL OF MACROPHAGE ACTIVATION, AND HOW WE ENVISION INTEGRATING STUDIES ON TRANSCRIPTIONAL AND EPIGENETIC REGULATION, AND MORE CLASSICAL APPROACHES IN MURINE MODELS. MOREOVER, WE PROVIDE NEW INSIGHTS INTO HOW WE CAN LEARN ABOUT TRANSCRIPTIONAL REGULATION IN THE HUMAN SYSTEM FROM LARGER EFFORTS SUCH AS THE FANTOM (FUNCTIONAL ANNOTATION OF THE MAMMALIAN GENOME) CONSORTIUM. 2015 16 3436 21 HYPERGLYCEMIC MEMORY OF INNATE IMMUNE CELLS PROMOTES IN VITRO PROINFLAMMATORY RESPONSES OF HUMAN MONOCYTES AND MURINE MACROPHAGES. IT HAS BEEN WELL ESTABLISHED THAT THE PRESENCE OF DIABETES IS ACCOMPANIED BY A CHRONIC INFLAMMATORY STATE PROMOTING VARIOUS DIABETES-ASSOCIATED COMPLICATIONS. ONE POTENTIAL DRIVER OF THIS ENHANCED INFLAMMATORY STATE IN PATIENTS WITH DIABETES IS HYPERGLYCEMIA. EVEN AFTER BLOOD GLUCOSE CONTROL IS ACHIEVED, DIABETES-ASSOCIATED COMPLICATIONS PERSIST, SUGGESTING THE PRESENCE OF A "HYPERGLYCEMIC MEMORY." INNATE IMMUNE CELLS, CRITICALLY INVOLVED IN VARIOUS COMPLICATIONS ASSOCIATED WITH DIABETES, CAN BUILD NONSPECIFIC, IMMUNOLOGICAL MEMORY (TRAINED IMMUNITY) VIA EPIGENETIC REGULATION. WE EXAMINE THE POTENTIAL INVOLVEMENT OF HYPERGLYCEMIA-INDUCED TRAINED IMMUNITY IN PROMOTING INFLAMMATION. OUR RESULTS SHOW THAT HYPERGLYCEMIA INDUCES A TRAINED PHENOTYPE IN VIVO IN MICE AND IN VITRO IN HUMAN MONOCYTES, REPRESENTATIVE BY AN INCREASED TNF-ALPHA SECRETION AFTER EX VIVO STIMULATION WITH LPS. THESE EFFECTS WERE LARGELY MEDIATED BY EPIGENETIC CHANGES CONTROLLED BY THE MIXED LINEAGE LEUKEMIA (MLL) FAMILY BECAUSE TREATMENT WITH THE MLL INHIBITOR MENIN-MLL DURING THE PROCESS OF TRAINED IMMUNITY ACQUISITION REPRESSED THE PROINFLAMMATORY PHENOTYPE. COLLECTIVELY, OUR RESULTS IDENTIFY A NOVEL LINK BETWEEN HYPERGLYCEMIA AND INFLAMMATION IN INNATE IMMUNE CELLS THAT MIGHT EXPLAIN THE INCREASED PROINFLAMMATORY STATE DURING DIABETES POTENTIALLY CONTRIBUTING TO THE DEVELOPMENT OF VARIOUS DIABETES-ASSOCIATED COMPLICATIONS. 2021 17 4738 37 NOVEL FIBROBLAST PHENOTYPES IN HOMEOSTASIS AND CHRONIC INFLAMMATION: FROM FUNCTIONS TO POTENTIAL REGULATORS. FIBROBLASTS ARE ESSENTIAL COMPONENTS OF THE STROMA, SUSTAINING A VARIETY OF TISSUES AND BEING KEY TO THE PROCESS OF TISSUE REPAIR AFTER INJURY. THEIR ROLE IN TISSUE REPAIR HAS BEEN ATTRIBUTED TO THEIR ABILITY TO ACQUIRE A CONTRACTILE, EXTRACELLULAR MATRIX-PRODUCING PHENOTYPE KNOWN AS MYOFIBROBLASTS. THIS PROPERTY IS PRIMARILY DEPENDENT ON THEIR RESPONSE TO THE PLEIOTROPIC CYTOKINE TRANSFORMING GROWTH FACTOR-BETA1. UNTIL RECENTLY, THE POTENTIAL ROLE OF FIBROBLASTS IN OTHER HOMEOSTATIC AND DISEASE-RELATED PROCESSES WAS LESS WELL UNDERSTOOD. ALTHOUGH IN VITRO STUDIES INDICATED THAT FIBROBLASTS ARE ABLE TO RESPOND TO AND SECRETE INFLAMMATORY MEDIATORS, DEFINITIVE EVIDENCE OF THEIR CONTRIBUTION TO CHRONIC INFLAMMATION WAS LIMITED. HOWEVER, THE EMERGENCE OF TECHNIQUES THAT ALLOW EXPLORATION OF TISSUES AT THE SINGLE CELL LEVEL HAS CHALLENGED THE PREVIOUS PARADIGMS ON FIBROBLAST IDENTITY AND FUNCTIONS, AND HAS LED TO THE DISCOVERY OF SIGNIFICANT DIVERSITY, SHOWING THE PRESENCE OF FIBROBLASTS WITH ALTERNATE TRANSCRIPTIONAL PROFILES IN A VARIETY OF TISSUES. THESE STUDIES HAVE ALSO SUGGESTED POTENTIAL ROLES OF NOVEL FIBROBLAST SUBTYPES AS REGULATORS OF EPITHELIAL HOMEOSTASIS AND RENEWAL, INFLAMMATORY CELL INFILTRATION AND ACTIVATION, AND ANTIGEN PRESENTATION. HERE, WE PROVIDE A COMPREHENSIVE REVIEW OF THE RECENT LITERATURE ON FIBROBLAST DIVERSITY IN THE DIGESTIVE TRACT, SKIN, LUNGS AND JOINTS. WE ALSO REVIEW EVIDENCE OF THEIR CONTRIBUTION TO THE REGULATION OF HOMEOSTASIS AND CHRONIC INFLAMMATION, AS WELL AS THEIR INTERACTIONS WITH OTHER CELLS IN VARIOUS TISSUE COMPARTMENTS. WE DISCUSS EVIDENCE OF DIFFERENT FACTORS INVOLVED IN THE CONTROL OF FIBROBLAST FUNCTION, ADDRESSING THE ROLE OF VARIOUS CYTOKINES, TRANSCRIPTION FACTORS AND EPIGENETIC CHANGES, AS WELL AS MICROENVIRONMENTAL FACTORS, INCLUDING EXTRACELLULAR MATRIX STIFFNESS, HYPOXIA, AND METABOLIC SHIFTS. 2023 18 4434 17 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 19 3661 27 INDUCTION OF INNATE IMMUNE MEMORY BY ENGINEERED NANOPARTICLES IN MONOCYTES/MACROPHAGES: FROM HYPOTHESIS TO REALITY. THE CAPACITY OF ENGINEERED NANOPARTICLES TO ACTIVATE CELLS OF THE INNATE IMMUNE SYSTEM, IN PARTICULAR MONOCYTES AND MACROPHAGES, IS CONSIDERED AT THE BASIS OF THEIR TOXIC/INFLAMMATORY EFFECTS. IT IS, HOWEVER, EVIDENT THAT EVEN NANOPARTICLES THAT DO NOT DIRECTLY INDUCE INFLAMMATORY ACTIVATION, AND ARE THEREFORE CONSIDERED AS SAFE, CAN NEVERTHELESS INDUCE EPIGENETIC MODIFICATIONS AND AFFECT METABOLIC PATHWAYS IN MONOCYTES AND MACROPHAGES. SINCE EPIGENETIC AND METABOLIC CHANGES ARE THE MAIN MECHANISMS OF INNATE MEMORY, WE HAD PREVIOUSLY PROPOSED THAT NANOPARTICLES CAN INDUCE/MODULATE INNATE MEMORY, THAT IS, HAVE THE ABILITY OF SHAPING THE SECONDARY RESPONSE TO INFLAMMATORY CHALLENGES. IN LIGHT OF NEW DATA, IT IS NOW POSSIBLE TO SUPPORT THE ORIGINAL HYPOTHESIS AND SHOW THAT DIFFERENT TYPES OF NANOPARTICLES CAN BOTH DIRECTLY INDUCE INNATE MEMORY, PRIMING MACROPHAGES FOR A MORE POTENT RESPONSE TO SUBSEQUENT STIMULI, AND MODULATE BACTERIA-INDUCED MEMORY BY ATTENUATING THE PRIMING-INDUCED ENHANCEMENT. THIS EVIDENCE RAISES TWO IMPORTANT ISSUES. FIRST, IN ADDITION TO OVERT TOXIC/INFLAMMATORY EFFECTS, WE SHOULD CONSIDER EVALUATING THE CAPACITY TO INDUCE INNATE MEMORY AND THE RELATED EPIGENETIC AND METABOLIC CHANGES IN THE IMMUNOSAFETY ASSESSMENT OF NANOMATERIALS, SINCE MODULATION OF INNATE MEMORY MAY BE AT THE BASIS OF LONG-TERM UNWANTED IMMUNOLOGICAL EFFECTS. THE OTHER IMPORTANT CONSIDERATION IS THAT THIS CAPACITY OF NANOMATERIALS COULD OPEN A NEW AVENUE IN IMMUNOMODULATION AND THE POSSIBILITY OF USING ENGINEERED NANOMATERIALS FOR IMPROVING IMMUNE RESPONSES TO VACCINES AND RESISTANCE TO INFECTIONS, AND MODULATE ANOMALOUS IMMUNE/INFLAMMATORY REACTIONS IN CHRONIC INFLAMMATORY DISEASES, AUTOIMMUNITY, AND A RANGE OF OTHER IMMUNE-RELATED PATHOLOGIES. 2020 20 2056 24 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