1 5898 94 T(H)2 CELL DEVELOPMENT AND FUNCTION. T HELPER 2 (T(H)2) CELLS ORCHESTRATE PROTECTIVE TYPE 2 IMMUNE RESPONSES, SUCH AS THOSE THAT TARGET HELMINTHS AND FACILITATE TISSUE REPAIR, BUT ALSO CONTRIBUTE TO CHRONIC INFLAMMATORY DISEASES, SUCH AS ASTHMA AND ALLERGY. HERE, WE REVIEW RECENT INSIGHTS INTO HOW DIVERSE MOLECULAR SIGNALS FROM CELLULAR SOURCES, INCLUDING DENDRITIC CELLS, INNATE LYMPHOID CELLS AND THE EPITHELIUM, ARE INTEGRATED BY T CELLS TO GUIDE THE TRANSCRIPTIONAL AND EPIGENETIC CHANGES NECESSARY FOR T(H)2 CELL DIFFERENTIATION. OUR IMPROVED UNDERSTANDING OF THESE PATHWAYS HAS OPENED NEW AVENUES FOR THERAPEUTICALLY TARGETING T(H)2 CELLS IN ASTHMA AND ALLERGY. THE ADVENT OF COMPREHENSIVE SINGLE-CELL TRANSCRIPTOMICS ALONG WITH IMPROVEMENTS IN SINGLE-CELL PROTEOMICS AND THE GENERATION OF NOVEL IN VIVO CELL FATE MAPPING TECHNIQUES PROMISE TO EXPAND OUR UNDERSTANDING OF T CELL DIVERSITY AND OFFER NEW INSIGHT INTO DISEASE-RELATED HETEROGENEITY AND PLASTICITY OF T(H) CELL RESPONSES. 2018 2 6535 33 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 3 6500 33 TRAINED IMMUNITY IN TYPE 2 IMMUNE RESPONSES. IMMUNOLOGICAL MEMORY OF INNATE IMMUNE CELLS, ALSO TERMED "TRAINED IMMUNITY", ALLOWS FOR CROSS-PROTECTION AGAINST DISTINCT PATHOGENS, BUT MAY ALSO DRIVE CHRONIC INFLAMMATION. RECENT STUDIES HAVE SHOWN THAT MEMORY RESPONSES ASSOCIATED WITH TYPE 2 IMMUNITY DO NOT SOLELY RELY ON ADAPTIVE IMMUNE CELLS, SUCH AS T- AND B CELLS, BUT ALSO INVOLVE THE INNATE IMMUNE SYSTEM AND EPITHELIAL CELLS. MEMORY RESPONSES HAVE BEEN DESCRIBED FOR MONOCYTES, MACROPHAGES AND AIRWAY EPITHELIAL CELLS OF ASTHMATIC PATIENTS AS WELL AS FOR MACROPHAGES AND GROUP 2 INNATE LYMPHOID CELLS (ILC2) FROM ALLERGEN-SENSITIZED OR HELMINTH-INFECTED MICE. THE METABOLIC AND EPIGENETIC MECHANISMS THAT MEDIATE ALLERGEN- OR HELMINTH-INDUCED REPROGRAMMING OF INNATE IMMUNE CELLS ARE ONLY BEGINNING TO BE UNCOVERED. TRAINED IMMUNITY HAS BEEN IMPLICATED IN HELMINTH-DRIVEN IMMUNE REGULATION AND ALLERGEN-SPECIFIC IMMUNOTHERAPY, SUGGESTING ITS EXPLOITATION IN FUTURE THERAPIES. HERE, WE DISCUSS RECENT ADVANCES AND KEY REMAINING QUESTIONS REGARDING THE MECHANISMS AND FUNCTIONS OF TRAINED TYPE 2 IMMUNITY IN INFECTION AND INFLAMMATION. 2022 4 2344 30 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 5 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 6 1876 30 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 7 4434 24 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 8 4340 29 MIGRATION OF STEM-LIKE CD8 T CELLS BETWEEN TISSUE MICROENVIRONMENTS UNDERPINS SUCCESSFUL ANTI-TUMOUR IMMUNE RESPONSES. THE CLINICAL SUCCESS OF IMMUNE CHECKPOINT BLOCKADE IN SOME PATIENTS HAS TRANSFORMED TREATMENT APPROACHES IN CANCER AND OFFERS THE HOPE OF DURABLE CURATIVE RESPONSES. BUILDING FROM STUDIES OF CHRONIC INFECTION, THE COMPOSITION OF TUMOUR INFILTRATING LYMPHOCYTES AND IN PARTICULAR, THE SPECTRUM OF EXHAUSTED CD8 T CELLS HAS NOW BEEN CHARACTERIZED IN DETAIL, PROFILING THE PHENOTYPE, FUNCTION, TRANSCRIPTIONAL REGULATION AND EVEN THE EPIGENETIC CHANGES. HOWEVER, WHAT REMAINS LESS CLEAR IS HOW INTRATUMOURAL IMMUNE CELLS INTERFACE WITH POPULATIONS IN THE PERIPHERY, BOTH IN TERMS OF SUSTAINING THE RESPONSE IN CANCER, BUT ALSO IN ESTABLISHING SYSTEMIC MEMORY RESPONSES THAT CAN PROVIDE LONG-TERM PROTECTION. HERE WE WILL SUCCINCTLY REVIEW THE CURRENT UNDERSTANDING OF THE ANTI-TUMOUR RESPONSE, CONSIDER THE TISSUE MICROENVIRONMENTS THAT SUPPORT KEY CELLULAR SUBSETS AND THE EXTENT TO WHICH CELLULAR MIGRATION BETWEEN THESE SITES IMPACTS THE RESPONSE. 2023 9 6014 27 THE ARCHITECTURAL DESIGN OF CD8+ T CELL RESPONSES IN ACUTE AND CHRONIC INFECTION: PARALLEL STRUCTURES WITH DIVERGENT FATES. IN RESPONSE TO INFECTION, T CELLS ADOPT A RANGE OF DIFFERENTIATION STATES, CREATING NUMEROUS HETEROGENEOUS SUBSETS THAT EXHIBIT DIFFERENT PHENOTYPES, FUNCTIONS, AND MIGRATION PATTERNS. THIS T CELL HETEROGENEITY IS A UNIVERSAL FEATURE OF T CELL IMMUNITY, NEEDED TO EFFECTIVELY CONTROL PATHOGENS IN A CONTEXT-DEPENDENT MANNER AND GENERATE LONG-LIVED IMMUNITY TO THOSE PATHOGENS. HERE, WE REVIEW NEW INSIGHTS INTO DIFFERENTIATION STATE DYNAMICS AND POPULATION HETEROGENEITY OF CD8+ T CELLS IN ACUTE AND CHRONIC VIRAL INFECTIONS AND CANCER AND HIGHLIGHT THE PARALLELS AND DISTINCTIONS BETWEEN ACUTE AND CHRONIC ANTIGEN STIMULATION SETTINGS. WE FOCUS ON TRANSCRIPTIONAL AND EPIGENETIC NETWORKS THAT MODULATE THE PLASTICITY AND TERMINAL DIFFERENTIATION OF ANTIGEN-SPECIFIC CD8+ T CELLS AND GENERATE FUNCTIONALLY DIVERSE T CELL SUBSETS WITH DIFFERENT ROLES TO COMBAT INFECTION AND CANCER. 2021 10 5896 35 T CELLS IN HEALTH AND DISEASE. T CELLS ARE CRUCIAL FOR IMMUNE FUNCTIONS TO MAINTAIN HEALTH AND PREVENT DISEASE. T CELL DEVELOPMENT OCCURS IN A STEPWISE PROCESS IN THE THYMUS AND MAINLY GENERATES CD4(+) AND CD8(+) T CELL SUBSETS. UPON ANTIGEN STIMULATION, NAIVE T CELLS DIFFERENTIATE INTO CD4(+) HELPER AND CD8(+) CYTOTOXIC EFFECTOR AND MEMORY CELLS, MEDIATING DIRECT KILLING, DIVERSE IMMUNE REGULATORY FUNCTION, AND LONG-TERM PROTECTION. IN RESPONSE TO ACUTE AND CHRONIC INFECTIONS AND TUMORS, T CELLS ADOPT DISTINCT DIFFERENTIATION TRAJECTORIES AND DEVELOP INTO A RANGE OF HETEROGENEOUS POPULATIONS WITH VARIOUS PHENOTYPE, DIFFERENTIATION POTENTIAL, AND FUNCTIONALITY UNDER PRECISE AND ELABORATE REGULATIONS OF TRANSCRIPTIONAL AND EPIGENETIC PROGRAMS. ABNORMAL T-CELL IMMUNITY CAN INITIATE AND PROMOTE THE PATHOGENESIS OF AUTOIMMUNE DISEASES. IN THIS REVIEW, WE SUMMARIZE THE CURRENT UNDERSTANDING OF T CELL DEVELOPMENT, CD4(+) AND CD8(+) T CELL CLASSIFICATION, AND DIFFERENTIATION IN PHYSIOLOGICAL SETTINGS. WE FURTHER ELABORATE THE HETEROGENEITY, DIFFERENTIATION, FUNCTIONALITY, AND REGULATION NETWORK OF CD4(+) AND CD8(+) T CELLS IN INFECTIOUS DISEASE, CHRONIC INFECTION AND TUMOR, AND AUTOIMMUNE DISEASE, HIGHLIGHTING THE EXHAUSTED CD8(+) T CELL DIFFERENTIATION TRAJECTORY, CD4(+) T CELL HELPER FUNCTION, T CELL CONTRIBUTIONS TO IMMUNOTHERAPY AND AUTOIMMUNE PATHOGENESIS. WE ALSO DISCUSS THE DEVELOPMENT AND FUNCTION OF GAMMADELTA T CELLS IN TISSUE SURVEILLANCE, INFECTION, AND TUMOR IMMUNITY. FINALLY, WE SUMMARIZED CURRENT T-CELL-BASED IMMUNOTHERAPIES IN BOTH CANCER AND AUTOIMMUNE DISEASES, WITH AN EMPHASIS ON THEIR CLINICAL APPLICATIONS. A BETTER UNDERSTANDING OF T CELL IMMUNITY PROVIDES INSIGHT INTO DEVELOPING NOVEL PROPHYLACTIC AND THERAPEUTIC STRATEGIES IN HUMAN DISEASES. 2023 11 3703 30 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 12 2925 39 GENERATING LONG-LIVED CD8(+) T-CELL MEMORY: INSIGHTS FROM EPIGENETIC PROGRAMS. T-CELL-BASED IMMUNOLOGICAL MEMORY HAS THE POTENTIAL TO PROVIDE THE HOST WITH LIFE-LONG PROTECTION AGAINST PATHOGEN REEXPOSURE AND THUS OFFERS TREMENDOUS PROMISE FOR THE DESIGN OF VACCINES TARGETING CHRONIC INFECTIONS OR CANCER. IN ORDER TO EXPLOIT THIS POTENTIAL IN THE DESIGN OF NEW VACCINES, IT IS NECESSARY TO UNDERSTAND HOW AND WHEN MEMORY T CELLS ACQUIRE THEIR POISED EFFECTOR POTENTIAL, AND MOREOVER, HOW THEY MAINTAIN THESE PROPERTIES DURING HOMEOSTATIC PROLIFERATION. TO GAIN INSIGHT INTO THE PERSISTENT NATURE OF MEMORY T-CELL FUNCTIONS, INVESTIGATORS HAVE TURNED THEIR ATTENTION TO EPIGENETIC MECHANISMS. RECENT EFFORTS HAVE REVEALED THAT MANY OF THE PROPERTIES ACQUIRED AMONG MEMORY T CELLS ARE COUPLED TO STABLE CHANGES IN DNA METHYLATION AND HISTONE MODIFICATIONS. FURTHERMORE, IT HAS RECENTLY BEEN REPORTED THAT THE DELINEATING FEATURES AMONG MEMORY T CELLS SUBSETS ARE ALSO LINKED TO DISTINCT EPIGENETIC EVENTS, SUCH AS PERMISSIVE AND REPRESSIVE HISTONE MODIFICATIONS AND DNA METHYLATION PROGRAMS, PROVIDING EXCITING NEW HYPOTHESES REGARDING THEIR CELLULAR ANCESTRY. HERE, WE REVIEW RECENT STUDIES FOCUSED ON EPIGENETIC PROGRAMS ACQUIRED DURING EFFECTOR AND MEMORY T-CELL DIFFERENTIATION AND DISCUSS HOW THESE DATA MAY SHED NEW LIGHT ON THE DEVELOPMENTAL PATH FOR GENERATING LONG-LIVED CD8(+) T-CELL MEMORY. 2016 13 4738 38 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 14 2070 19 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 15 5996 34 TH2 CELLS IN HEALTH AND DISEASE. HELPER T (TH) CELL SUBSETS DIRECT IMMUNE RESPONSES BY PRODUCING SIGNATURE CYTOKINES. TH2 CELLS PRODUCE IL-4, IL-5, AND IL-13, WHICH ARE IMPORTANT IN HUMORAL IMMUNITY AND PROTECTION FROM HELMINTH INFECTION AND ARE CENTRAL TO THE PATHOGENESIS OF MANY ALLERGIC INFLAMMATORY DISEASES. MOLECULAR ANALYSIS OF TH2 CELL DIFFERENTIATION AND MAINTENANCE OF FUNCTION HAS LED TO RECENT DISCOVERIES THAT HAVE REFINED OUR UNDERSTANDING OF TH2 CELL BIOLOGY. EPIGENETIC REGULATION OF GATA3 EXPRESSION BY CHROMATIN REMODELING COMPLEXES SUCH AS POLYCOMB AND TRITHORAX IS CRUCIAL FOR MAINTAINING TH2 CELL IDENTITY. IN THE CONTEXT OF ALLERGIC DISEASES, MEMORY-TYPE PATHOGENIC TH2 CELLS HAVE BEEN IDENTIFIED IN BOTH MICE AND HUMANS. TO BETTER UNDERSTAND THESE DISEASE-DRIVING CELL POPULATIONS, WE HAVE DEVELOPED A MODEL CALLED THE PATHOGENIC TH POPULATION DISEASE INDUCTION MODEL. THE CONCEPT OF DEFINED SUBSETS OF PATHOGENIC TH CELLS MAY SPUR NEW, EFFECTIVE STRATEGIES FOR TREATING INTRACTABLE CHRONIC INFLAMMATORY DISORDERS. 2017 16 5412 28 REGULATION OF ANTITUMOR IMMUNITY BY INFLAMMATION-INDUCED EPIGENETIC ALTERATIONS. CHRONIC INFLAMMATION PROMOTES TUMOR DEVELOPMENT, PROGRESSION, AND METASTATIC DISSEMINATION AND CAUSES TREATMENT RESISTANCE. THE ACCUMULATION OF GENETIC ALTERATIONS AND LOSS OF NORMAL CELLULAR REGULATORY PROCESSES ARE NOT ONLY ASSOCIATED WITH CANCER GROWTH AND PROGRESSION BUT ALSO RESULT IN THE EXPRESSION OF TUMOR-SPECIFIC AND TUMOR-ASSOCIATED ANTIGENS THAT MAY ACTIVATE ANTITUMOR IMMUNITY. THIS ANTAGONISM BETWEEN INFLAMMATION AND IMMUNITY AND THE ABILITY OF CANCER CELLS TO AVOID IMMUNE DETECTION AFFECT THE COURSE OF CANCER DEVELOPMENT AND TREATMENT OUTCOMES. WHILE INFLAMMATION, PARTICULARLY ACUTE INFLAMMATION, SUPPORTS T-CELL PRIMING, ACTIVATION, AND INFILTRATION INTO INFECTED TISSUES, CHRONIC INFLAMMATION IS MOSTLY IMMUNOSUPPRESSIVE. HOWEVER, THE MAIN MECHANISMS THAT DICTATE THE OUTCOME OF THE INFLAMMATION-IMMUNITY INTERPLAY ARE NOT WELL UNDERSTOOD. RECENT DATA SUGGEST THAT INFLAMMATION TRIGGERS EPIGENETIC ALTERATIONS IN CANCER CELLS AND COMPONENTS OF THE TUMOR MICROENVIRONMENT. THESE ALTERATIONS CAN AFFECT AND MODULATE NUMEROUS ASPECTS OF CANCER DEVELOPMENT, INCLUDING TUMOR GROWTH, THE METABOLIC STATE, METASTATIC SPREAD, IMMUNE ESCAPE, AND IMMUNOSUPPRESSIVE OR IMMUNOSUPPORTIVE LEUKOCYTE GENERATION. IN THIS REVIEW, WE DISCUSS THE ROLE OF INFLAMMATION IN INITIATING EPIGENETIC ALTERATIONS IN IMMUNE CELLS, CANCER-ASSOCIATED FIBROBLASTS, AND CANCER CELLS AND SUGGEST HOW AND WHEN EPIGENETIC INTERVENTIONS CAN BE COMBINED WITH IMMUNOTHERAPIES TO IMPROVE THERAPEUTIC OUTCOMES. 2022 17 2299 37 EPIGENETIC REGULATION OF AIRWAY EPITHELIUM IMMUNE FUNCTIONS IN ASTHMA. ASTHMA IS A CHRONIC INFLAMMATORY DISEASE OF THE RESPIRATORY TRACT CHARACTERIZED BY RECURRENT BREATHING PROBLEMS RESULTING FROM AIRWAY OBSTRUCTION AND HYPERRESPONSIVENESS. HUMAN AIRWAY EPITHELIUM PLAYS AN IMPORTANT ROLE IN THE INITIATION AND CONTROL OF THE IMMUNE RESPONSES TO DIFFERENT TYPES OF ENVIRONMENTAL FACTORS CONTRIBUTING TO ASTHMA PATHOGENESIS. USING PATTERN RECOGNITION RECEPTORS AIRWAY EPITHELIUM SENSES EXTERNAL STIMULI, SUCH AS ALLERGENS, MICROBES, OR POLLUTANTS, AND SUBSEQUENTLY SECRETES ENDOGENOUS DANGER SIGNALING MOLECULES ALARMING AND ACTIVATING DENDRITIC CELLS. HENCE, AIRWAY EPITHELIAL CELLS NOT ONLY MEDIATE INNATE IMMUNE RESPONSES BUT ALSO BRIDGE THEM WITH ADAPTIVE IMMUNE RESPONSES INVOLVING T AND B CELLS THAT PLAY A CRUCIAL ROLE IN THE PATHOGENESIS OF ASTHMA. THE EFFECTS OF ENVIRONMENTAL FACTORS ON THE DEVELOPMENT OF ASTHMA ARE MEDIATED, AT LEAST IN PART, BY EPIGENETIC MECHANISMS. THOSE COMPRISE CLASSICAL EPIGENETICS INCLUDING DNA METHYLATION AND HISTONE MODIFICATIONS AFFECTING TRANSCRIPTION, AS WELL AS MICRORNAS INFLUENCING TRANSLATION. THE COMMON FEATURE OF SUCH MECHANISMS IS THAT THEY REGULATE GENE EXPRESSION WITHOUT AFFECTING THE NUCLEOTIDE SEQUENCE OF THE GENOMIC DNA. EPIGENETIC MECHANISMS PLAY A PIVOTAL ROLE IN THE REGULATION OF DIFFERENT CELL POPULATIONS INVOLVED IN ASTHMA PATHOGENESIS, WITH THE REMARKABLE EXAMPLE OF T CELLS. RECENTLY, HOWEVER, THERE IS INCREASING EVIDENCE THAT EPIGENETIC MECHANISMS ARE ALSO CRUCIAL FOR THE REGULATION OF AIRWAY EPITHELIAL CELLS, ESPECIALLY IN THE CONTEXT OF EPIGENETIC TRANSFER OF ENVIRONMENTAL EFFECTS CONTRIBUTING TO ASTHMA PATHOGENESIS. IN THIS REVIEW, WE SUMMARIZE THE ACCUMULATING EVIDENCE FOR THIS VERY IMPORTANT ASPECT OF AIRWAY EPITHELIAL CELL PATHOBIOLOGY. 2020 18 6365 30 THE ROLE OF METABOLIC DYSFUNCTION IN T-CELL EXHAUSTION DURING CHRONIC VIRAL INFECTION. T CELLS ARE IMPORTANT COMPONENTS OF ADAPTIVE IMMUNITY THAT PROTECT THE HOST AGAINST INVADING PATHOGENS DURING INFECTION. UPON RECOGNIZING THE ACTIVATION SIGNALS, NAIVE AND/OR MEMORY T CELLS WILL INITIATE CLONAL EXPANSION, TRIGGER DIFFERENTIATION INTO EFFECTOR POPULATIONS AND TRAFFIC TO THE INFLAMED SITES TO ELIMINATE PATHOGENS. HOWEVER, IN CHRONIC VIRAL INFECTIONS, SUCH AS THOSE CAUSED BY HUMAN IMMUNODEFICIENCY VIRUS (HIV), HEPATITIS B AND C (HBV AND HCV), T CELLS EXHIBIT IMPAIRED FUNCTION AND BECOME DIFFICULT TO CLEAR PATHOGENS IN A STATE KNOWN AS T-CELL EXHAUSTION. THE ACTIVATION AND FUNCTION PERSISTENCE OF T CELLS DEMAND FOR DYNAMIC CHANGES IN CELLULAR METABOLISM TO MEET THEIR BIOENERGETIC AND BIOSYNTHETIC DEMANDS, ESPECIALLY THE AUGMENTATION OF AEROBIC GLYCOLYSIS, WHICH NOT ONLY PROVIDE EFFICIENT ENERGY GENERATION, BUT ALSO FUEL MULTIPLE BIOCHEMICAL INTERMEDIATES THAT ARE ESSENTIAL FOR NUCLEOTIDE, AMINO ACID, FATTY ACID SYNTHESIS AND MITOCHONDRIA FUNCTION. CHANGES IN CELLULAR METABOLISM ALSO AFFECT THE FUNCTION OF EFFECTORS T CELLS THROUGH MODIFYING EPIGENETIC SIGNATURES. IT IS WIDELY ACCEPTED THAT THE DYSFUNCTION OF T CELL METABOLISM CONTRIBUTES GREATLY TO T-CELL EXHAUSTION. HERE, WE REVIEWED RECENT FINDINGS ON T CELLS METABOLISM UNDER CHRONIC VIRAL INFECTION, SEEKING TO REVEAL THE ROLE OF METABOLIC DYSFUNCTION PLAYED IN T-CELL EXHAUSTION. 2022 19 3732 23 INNATE IMMUNE MEMORY AND THE HOST RESPONSE TO INFECTION. UNLIKE THE ADAPTIVE IMMUNE SYSTEM, THE INNATE IMMUNE SYSTEM HAS CLASSICALLY BEEN CHARACTERIZED AS BEING DEVOID OF MEMORY FUNCTIONS. HOWEVER, RECENT RESEARCH SHOWS THAT INNATE MYELOID AND LYMPHOID CELLS HAVE THE ABILITY TO RETAIN MEMORY OF PRIOR PATHOGEN EXPOSURE AND BECOME PRIMED TO ELICIT A ROBUST, BROAD-SPECTRUM RESPONSE TO SUBSEQUENT INFECTION. THIS PHENOMENON HAS BEEN TERMED INNATE IMMUNE MEMORY OR TRAINED IMMUNITY. INNATE IMMUNE MEMORY IS INDUCED VIA ACTIVATION OF PATTERN RECOGNITION RECEPTORS AND THE ACTIONS OF CYTOKINES ON HEMATOPOIETIC PROGENITORS AND STEM CELLS IN BONE MARROW AND INNATE LEUKOCYTES IN THE PERIPHERY. THE TRAINED PHENOTYPE IS INDUCED AND SUSTAINED VIA EPIGENETIC MODIFICATIONS THAT REPROGRAM TRANSCRIPTIONAL PATTERNS AND METABOLISM. THESE MODIFICATIONS AUGMENT ANTIMICROBIAL FUNCTIONS, SUCH AS LEUKOCYTE EXPANSION, CHEMOTAXIS, PHAGOCYTOSIS, AND MICROBIAL KILLING, TO FACILITATE AN AUGMENTED HOST RESPONSE TO INFECTION. ALTERNATIVELY, INNATE IMMUNE MEMORY MAY CONTRIBUTE TO THE PATHOGENESIS OF CHRONIC DISEASES, SUCH AS ATHEROSCLEROSIS AND ALZHEIMER'S DISEASE. 2022 20 2525 29 EPIGENETICS AND TRAINED IMMUNITY. SIGNIFICANCE: A GROWING BODY OF CLINICAL AND EXPERIMENTAL EVIDENCE HAS CHALLENGED THE TRADITIONAL UNDERSTANDING THAT ONLY THE ADAPTIVE IMMUNE SYSTEM CAN MOUNT IMMUNOLOGICAL MEMORY. RECENT FINDINGS DESCRIBE THE ADAPTIVE CHARACTERISTICS OF THE INNATE IMMUNE SYSTEM, UNDERSCORED BY ITS ABILITY TO REMEMBER ANTECEDENT FOREIGN ENCOUNTERS AND RESPOND IN A NONSPECIFIC SENSITIZED MANNER TO REINFECTION. THIS HAS BEEN TERMED TRAINED INNATE IMMUNITY. ALTHOUGH BENEFICIAL IN THE CONTEXT OF RECURRENT INFECTIONS, THIS MIGHT ACTUALLY CONTRIBUTE TO CHRONIC IMMUNE-MEDIATED DISEASES, SUCH AS ATHEROSCLEROSIS. RECENT ADVANCES: IN LINE WITH ITS PROPOSED ROLE IN SUSTAINING CELLULAR MEMORIES, EPIGENETIC REPROGRAMMING HAS EMERGED AS A CRITICAL DETERMINANT OF TRAINED IMMUNITY. RECENT TECHNOLOGICAL AND COMPUTATIONAL ADVANCES THAT IMPROVE UNBIASED ACQUISITION OF EPIGENOMIC PROFILES HAVE SIGNIFICANTLY ENHANCED OUR APPRECIATION FOR THE COMPLEXITIES OF CHROMATIN ARCHITECTURE IN THE CONTEXTS OF DIVERSE IMMUNOLOGICAL CHALLENGES. CRITICAL ISSUES: KEY TO RESOLVING THE DISTINCT CHROMATIN SIGNATURES OF INNATE IMMUNE MEMORY IS A COMPREHENSIVE UNDERSTANDING OF THE PRECISE PHYSIOLOGICAL TARGETS OF REGULATORY PROTEINS THAT RECOGNIZE, DEPOSIT, AND REMOVE CHEMICAL MODIFICATIONS FROM CHROMATIN AS WELL AS OTHER GENE-REGULATING FACTORS. DRAWING FROM A RAPIDLY EXPANDING COMPENDIUM OF EXPERIMENTAL AND CLINICAL STUDIES, THIS REVIEW DETAILS A CURRENT PERSPECTIVE OF THE EPIGENETIC PATHWAYS THAT SUPPORT THE ADAPTED PHENOTYPES OF MONOCYTES AND MACROPHAGES. FUTURE DIRECTIONS: WE EXPLORE FUTURE STRATEGIES THAT ARE AIMED AT EXPLOITING THE MECHANISM OF TRAINED IMMUNITY TO IMPROVE THE PREVENTION AND TREATMENT OF INFECTIONS AND IMMUNE-MEDIATED CHRONIC DISORDERS. 2018