1 233 66 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 2 5896 26 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 3 6014 18 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 4 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 5 6535 23 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 6 5407 23 REGULATION AND IMMUNOTHERAPEUTIC TARGETING OF THE EPIGENOME IN EXHAUSTED CD8 T CELL RESPONSES. EXHAUSTION IS A STATE OF CD8 T CELL DIFFERENTIATION THAT OCCURS IN SETTINGS OF CHRONIC AG SUCH AS TUMORS, CHRONIC VIRAL INFECTION, AND AUTOIMMUNITY. CELLULAR DIFFERENTIATION IS DRIVEN BY A SERIES OF ENVIRONMENTAL SIGNALS THAT PROMOTE EPIGENETIC LANDSCAPES THAT SET TRANSCRIPTOMES NEEDED FOR FUNCTION. FOR CD8 T CELLS, THE EPIGENOME THAT UNDERLIES EXHAUSTION IS DISTINCT FROM EFFECTOR AND MEMORY CELL DIFFERENTIATION, SUGGESTING THAT SIGNALS EARLY ON SET IN MOTION A PROCESS WHERE THE EPIGENOME IS MODIFIED TO PROMOTE A TRAJECTORY TOWARD A DYSFUNCTIONAL STATE. ALTHOUGH WE KNOW MANY SIGNALS THAT PROMOTE EXHAUSTION, PUTTING THIS IN THE CONTEXT OF THE EPIGENETIC CHANGES THAT OCCUR DURING DIFFERENTIATION HAS BEEN LESS CLEAR. IN THIS REVIEW, WE AIM TO SUMMARIZE THE EPIGENETIC CHANGES ASSOCIATED WITH EXHAUSTION IN THE CONTEXT OF SIGNALS THAT PROMOTE IT, HIGHLIGHTING IMMUNOTHERAPEUTIC STUDIES THAT SUPPORT THESE OBSERVATIONS OR AREAS FOR FUTURE THERAPEUTIC OPPORTUNITIES. 2023 7 6677 20 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 8 1876 23 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 9 6365 18 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 10 2056 18 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 11 4200 31 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 12 451 21 APPLICATION OF ATAC-SEQ IN TUMOR-SPECIFIC T CELL EXHAUSTION. RESEARCHES SHOW THAT CHRONIC VIRAL INFECTION AND PERSISTENT ANTIGEN AND/OR INFLAMMATORY SIGNAL EXPOSURE IN CANCER CAUSES THE FUNCTIONAL STATUS OF T CELLS TO BE ALTERED, MAINLY BY MAJOR CHANGES IN THE EPIGENETIC AND METABOLIC ENVIRONMENT, WHICH THEN LEADS TO T CELL EXHAUSTION. THE DISCOVERY OF THE IMMUNE CHECKPOINT PATHWAY IS AN IMPORTANT MILESTONE IN UNDERSTANDING AND REVERSING T CELL EXHAUSTION. ANTIBODIES TARGETING THESE PATHWAYS HAVE SHOWN SUPERIOR ABILITY TO REVERSE T CELL EXHAUSTION. HOWEVER, THERE ARE STILL SOME LIMITATIONS IN IMMUNE CHECKPOINT BLOCKING THERAPY, SUCH AS THE SHORT-TERM NATURE OF THERAPEUTIC EFFECTS AND HIGH INDIVIDUAL HETEROGENEITY. ASSAY FOR TRANSPOSASE-ACCESSIBLE CHROMATIN WITH SEQUENCING(ATAC-SEQ) IS A METHOD USED TO ANALYZE THE ACCESSIBILITY OF WHOLE-GENOME CHROMATIN. IT USES HYPERACTIVE TN5 TRANSPOSASE TO ASSESS CHROMATIN ACCESSIBILITY. RECENTLY, A GROWING NUMBER OF STUDIES HAVE REPORTED THAT ATAC-SEQ CAN BE USED TO CHARACTERIZE THE DYNAMIC CHANGES OF EPIGENETICS IN THE PROCESS OF T CELL EXHAUSTION. IT HAS BEEN DETERMINED THAT IMMUNE CHECKPOINT BLOCKING CAN ONLY TEMPORARILY RESTORE THE FUNCTION OF EXHAUSTED T CELLS BECAUSE OF AN IRREVERSIBLE CHANGE IN THE EPIGENETICS OF EXHAUSTED T CELLS. IN THIS STUDY, WE REVIEW THE LATEST DEVELOPMENTS, WHICH PROVIDE A CLEARER MOLECULAR UNDERSTANDING OF T CELL EXHAUSTION, REVEAL POTENTIAL NEW THERAPEUTIC TARGETS FOR PERSISTENT VIRAL INFECTION AND CANCER, AND PROVIDE NEW INSIGHTS FOR DESIGNING EFFECTIVE IMMUNOTHERAPY FOR TREATING CANCER AND CHRONIC INFECTION. 2023 13 4340 18 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 14 5414 21 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 15 2145 15 EPIGENETIC MAINTENANCE OF ACQUIRED GENE EXPRESSION PROGRAMS DURING MEMORY CD8 T CELL HOMEOSTASIS. MEMORY CD8 T CELLS HAVE A UNIQUE ABILITY TO PROVIDE LIFELONG IMMUNITY AGAINST PATHOGENS CONTAINING THEIR COGNATE EPITOPE. BECAUSE OF THEIR ABILITY TO PROVIDE LIFELONG PROTECTION, THE GENERATION OF MEMORY T CELLS IS NOW A MAJOR FOCUS FOR CURRENT VACCINATION OR ADOPTIVE CELL THERAPY APPROACHES TO TREAT CHRONIC VIRAL INFECTIONS AND CANCER. IT IS NOW CLEAR THAT MAINTENANCE OF MEMORY CD8 T CELLS OCCURS THROUGH A PROCESS OF ANTIGEN-INDEPENDENT HOMEOSTATIC PROLIFERATION, WHICH IS REGULATED IN PART BY THE GAMMA CHAIN CYTOKINES IL-7 AND IL-15. HERE, WE WILL DESCRIBE THE ROLE OF THESE CYTOKINES IN THE SURVIVAL AND SELF-RENEWAL OF MEMORY CD8 T CELLS. FURTHER, WE WILL DESCRIBE THE ROLE OF EPIGENETICS IN THE MAINTENANCE OF ACQUIRED FUNCTIONS AMONG MEMORY CD8 T CELLS DURING HOMEOSTATIC PROLIFERATION. 2018 16 3732 18 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 17 6851 26 [MOLECULAR PROFILES OF EXHAUSTED T CELLS AND THEIR IMPACT ON RESPONSE TO IMMUNE CHECKPOINT BLOCKADE]. T CELL EXHAUSTION IS INDUCED IN THE CONTEXT OF CHRONIC VIRUS INFECTION AND TUMOR MICROENVIRONMENT, IN WHICH CYTOTOXIC T CELLS ARE REPEATEDLY EXPOSED TO THE TARGET ANTIGEN AND DEPRIVED OF THEIR EFFECTOR FUNCTIONS. MULTIPLE STUDIES HAVE ALREADY SHOWN THE SIGNIFICANT IMPACT OF IMMUNE CHECKPOINT MOLECULES SUCH AS PD1 ON FUNCTIONAL PROPERTIES OF EXHAUSTED T CELLS. IN ADDITION TO THESE SIGNALS, EXHAUSTED T CELLS POSSESS DISTINCT TRANSCRIPTIONAL AND EPIGENETIC PROFILES COMPARED WITH CONVENTIONAL EFFECTOR AND MEMORY T CELLS. IMPORTANTLY, MOST OF THESE FEATURES ARE NOT AFFECTED BY IMMUNE CHECKPOINT BLOCKADE, SUGGESTING THAT GENETIC AND EPIGENETIC REMODELING OF T CELLS IS AN UNDERLYING MOLECULAR MECHANISM ESSENTIAL FOR T CELL EXHAUSTION. MOREOVER, IT HAS NOW BEEN EVIDENT THAT EXHAUSTED T CELLS ARE A HETEROGENEOUS CELL POPULATION COMPOSED OF DISTINCT T CELL SUBSETS, AND THESE FUNCTIONAL DIFFERENCES PROFOUNDLY AFFECT THERAPEUTIC EFFICACY OF CANCER IMMUNOTHERAPY. IN THIS REVIEW, I WILL DISCUSS RECENT STUDIES INVESTIGATING MOLECULAR MECHANISMS OF T CELL EXHAUSTION, INCLUDING NOVEL KEY MOLECULES ESSENTIALLY ASSOCIATED WITH T CELL EXHAUSTION. THESE FINDINGS ARE POTENTIALLY APPLICABLE TO REINVIGORATE EFFECTOR FUNCTIONS OF EXHAUSTED T CELLS. 2022 18 3731 22 INNATE AND ADAPTIVE IMMUNE REGULATION DURING CHRONIC VIRAL INFECTIONS. CHRONIC VIRAL INFECTIONS REPRESENT A UNIQUE CHALLENGE TO THE INFECTED HOST. PERSISTENTLY REPLICATING VIRUSES OUTCOMPETE OR SUBVERT THE INITIAL ANTIVIRAL RESPONSE, ALLOWING THE ESTABLISHMENT OF CHRONIC INFECTIONS THAT RESULT IN CONTINUOUS STIMULATION OF BOTH THE INNATE AND ADAPTIVE IMMUNE COMPARTMENTS. THIS CAUSES A PROFOUND REPROGRAMMING OF THE HOST IMMUNE SYSTEM, INCLUDING ATTENUATION AND PERSISTENT LOW LEVELS OF TYPE I INTERFERONS, PROGRESSIVE LOSS (OR EXHAUSTION) OF CD8(+) T CELL FUNCTIONS, AND SPECIALIZATION OF CD4(+) T CELLS TO PRODUCE INTERLEUKIN-21 AND PROMOTE ANTIBODY-MEDIATED IMMUNITY AND IMMUNE REGULATION. EPIGENETIC, TRANSCRIPTIONAL, POSTTRANSCRIPTIONAL, AND METABOLIC CHANGES UNDERLIE THIS ADAPTATION OR RECALIBRATION OF IMMUNE CELLS TO THE EMERGING NEW ENVIRONMENT IN ORDER TO STRIKE AN OFTEN IMPERFECT BALANCE BETWEEN THE HOST AND THE INFECTIOUS PATHOGEN. IN THIS REVIEW WE DISCUSS THE COMMON IMMUNOLOGICAL HALLMARKS OBSERVED ACROSS A RANGE OF DIFFERENT PERSISTENTLY REPLICATING VIRUSES AND HOST SPECIES, THE UNDERLYING MOLECULAR MECHANISMS, AND THE BIOLOGICAL AND CLINICAL IMPLICATIONS. 2015 19 3895 23 LANDSCAPES AND MECHANISMS OF CD8(+) T CELL EXHAUSTION IN GASTROINTESTINAL CANCER. CD8(+) T CELLS, A CYTOTOXIC T LYMPHOCYTE, ARE A KEY COMPONENT OF THE TUMOR IMMUNE SYSTEM, BUT THEY ENTER A HYPOREACTIVE T CELL STATE IN LONG-TERM CHRONIC INFLAMMATION, AND HOW TO RESCUE THIS DEPLETED STATE IS A KEY DIRECTION OF RESEARCH. CURRENT STUDIES ON CD8(+) T CELL EXHAUSTION HAVE FOUND THAT THE MECHANISMS RESPONSIBLE FOR THEIR HETEROGENEITY AND DIFFERENTIAL KINETICS MAY BE CLOSELY RELATED TO TRANSCRIPTION FACTORS AND EPIGENETIC REGULATION, WHICH MAY SERVE AS BIOMARKERS AND POTENTIAL IMMUNOTHERAPEUTIC TARGETS TO GUIDE TREATMENT. ALTHOUGH THE IMPORTANCE OF T CELL EXHAUSTION IN TUMOR IMMUNOTHERAPY CANNOT BE OVERSTATED, STUDIES HAVE POINTED OUT THAT GASTRIC CANCER TISSUES HAVE A BETTER ANTI-TUMOR T CELL COMPOSITION COMPARED TO OTHER CANCER TISSUES, WHICH MAY INDICATE THAT GASTROINTESTINAL CANCERS HAVE MORE PROMISING PROSPECTS FOR THE DEVELOPMENT OF PRECISION-TARGETED IMMUNOTHERAPY. THEREFORE, THE PRESENT STUDY WILL FOCUS ON THE MECHANISMS INVOLVED IN THE DEVELOPMENT OF CD8(+) T CELL EXHAUSTION, AND THEN REVIEW THE LANDSCAPES AND MECHANISMS OF T CELL EXHAUSTION IN GASTROINTESTINAL CANCER AS WELL AS CLINICAL APPLICATIONS, WHICH WILL PROVIDE A CLEAR VISION FOR THE DEVELOPMENT OF FUTURE IMMUNOTHERAPIES. 2023 20 2344 22 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