1 5414 117 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 2 2145 30 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 3 2056 32 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 4 6014 29 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 5 6851 36 [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 6 4049 34 MAKING MEMORIES THAT LAST A LIFETIME: HERITABLE FUNCTIONS OF SELF-RENEWING MEMORY CD8 T CELLS. CLONAL EXPANSION OF VIRUS-SPECIFIC NAIVE T CELLS DURING AN ACUTE VIRAL INFECTION RESULTS IN THE FORMATION OF MEMORY CD8 T CELLS THAT PROVIDE THE HOST WITH LONG-TERM PROTECTIVE IMMUNITY AGAINST THE PATHOGEN. MEMORY CD8 T CELLS DISPLAY ENHANCED EFFECTOR FUNCTIONS COMPARED WITH THEIR NAIVE PRECURSORS, ALLOWING THEM TO RESPOND MORE RAPIDLY AND EFFECTIVELY TO ANTIGEN RE-ENCOUNTER. THE ENHANCED FUNCTIONS OF MEMORY CD8 T CELLS ARE MEDIATED BY HERITABLE CHANGES IN GENE REGULATION. EXPRESSION OF SELECT TRANSCRIPTION FACTORS ALONG WITH LOCUS-SPECIFIC EPIGENETIC MODIFICATIONS ARE COUPLED TO AND ARE ESSENTIAL IN THE FORMATION OF MEMORY-SPECIFIC GENE EXPRESSION PATTERNS. HERE, WE WILL REVIEW THE CHANGES IN GENE EXPRESSION THAT ACCOMPANY DEVELOPMENT OF MEMORY CD8 T CELLS AND DISCUSS CHROMATIN MODIFICATIONS AS A POTENTIAL MEANS FOR HERITABLE PROPAGATION OF THESE CHANGES DURING HOMEOSTATIC CELL DIVISION OF SELF-RENEWING MEMORY CD8 T CELLS. ALSO, WE WILL DISCUSS THERAPIES THAT MANIPULATE HERITABLE GENE REGULATION AS A POTENTIAL MECHANISM TO RESTORE FUNCTION TO NON-FUNCTIONAL MEMORY CD8 T CELLS TO COMBAT CHRONIC VIRAL INFECTION. 2010 7 4196 30 METABOLIC PLASTICITY AND REGULATION OF T CELL EXHAUSTION. THE METABOLIC REPROGRAMMING DURING T CELL ACTIVATION AND DIFFERENTIATION AFFECTS T CELL FATE AND IMMUNE RESPONSES. CELL METABOLISM MAY SERVE AS THE DRIVING FORCE THAT INDUCES EPIGENETIC MODIFICATIONS, CONTRIBUTING TO REGULATING T CELL DIFFERENTIATION. PERSISTENT PATHOGEN INFECTION LEADS TO T CELL EXHAUSTION, WHICH IS COMPOSED OF TWO MAIN SUBSETS AND WITH DISTINCT METABOLIC CHARACTERISTICS. THE PROGENITOR EXHAUSTED T CELLS UTILIZE MITOCHONDRIAL FATTY ACID OXIDATION (FAO) AND OXIDATIVE PHOSPHORYLATION (OXPHOS) FOR ENERGY, WHILE TERMINALLY EXHAUSTED T CELLS MAINLY RELY ON GLYCOLYTIC METABOLISM WITH IMPAIRED GLYCOLYSIS AND OXPHOS. HERE, WE COMPILED THE LATEST RESEARCH ON HOW T CELL METABOLISM DEFINES DIFFERENTIATION, FOCUSING ON T CELL EXHAUSTION DURING CHRONIC INFECTIONS. IN ADDITION, METABOLIC-RELATED FACTORS INCLUDING ANTIGEN STIMULATION SIGNALS STRENGTH, CYTOKINES AND EPIGENETICS AFFECTING T CELL EXHAUSTION WERE ALSO REVIEWED. FURTHERMORE, THE INTERVENTION STRATEGIES ON METABOLISM AND EPIGENETICS TO REVERSE T CELL EXHAUSTION WERE DISCUSSED IN DETAIL, WHICH MAY CONTRIBUTE TO ACHIEVING THE GOAL OF PREVENTION AND TREATMENT OF T CELL EXHAUSTION. 2022 8 5896 37 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 9 2718 36 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 10 4726 23 NOT-SO-OPPOSITE ENDS OF THE SPECTRUM: CD8(+) T CELL DYSFUNCTION ACROSS CHRONIC INFECTION, CANCER AND AUTOIMMUNITY. CD8(+) T CELLS ARE CRITICAL MEDIATORS OF CYTOTOXIC EFFECTOR FUNCTION IN INFECTION, CANCER AND AUTOIMMUNITY. IN CANCER AND CHRONIC VIRAL INFECTION, CD8(+) T CELLS UNDERGO A PROGRESSIVE LOSS OF CYTOKINE PRODUCTION AND CYTOTOXICITY, A STATE TERMED T CELL EXHAUSTION. IN AUTOIMMUNITY, AUTOREACTIVE CD8(+) T CELLS RETAIN THE CAPACITY TO EFFECTIVELY MEDIATE THE DESTRUCTION OF HOST TISSUES. ALTHOUGH THE CLINICAL OUTCOME DIFFERS IN EACH CONTEXT, CD8(+) T CELLS ARE CHRONICALLY EXPOSED TO ANTIGEN IN ALL THREE. THESE CHRONICALLY STIMULATED CD8(+) T CELLS SHARE SOME COMMON PHENOTYPIC FEATURES, AS WELL AS TRANSCRIPTIONAL AND EPIGENETIC PROGRAMMING, ACROSS DISEASE CONTEXTS. A BETTER UNDERSTANDING OF THESE CD8(+) T CELL STATES MAY REVEAL NOVEL STRATEGIES TO AUGMENT CLEARANCE OF CHRONIC VIRAL INFECTION AND CANCER AND TO MITIGATE SELF-REACTIVITY LEADING TO TISSUE DAMAGE IN AUTOIMMUNITY. 2021 11 5407 36 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 12 451 34 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 6060 32 THE DEVELOPMENT OF CD8 T-CELL EXHAUSTION HETEROGENEITY AND THE THERAPEUTIC POTENTIALS IN CANCER. CD8(+) T CELLS ARE ESSENTIAL LYMPHOCYTES WITH CYTOTOXIC PROPERTIES FOR ANTITUMOR IMMUNOTHERAPY. HOWEVER, DURING CHRONIC INFECTION OR TUMORIGENESIS, THESE CELLS OFTEN BECOME DYSFUNCTIONAL WITH A GRADUALLY DEPLETED ABILITY TO RELEASE CYTOKINES AND THE EXHIBITION OF REDUCED CYTOTOXICITY, THE STATE REFERRED TO AS "T-CELL EXHAUSTION" (TEX). THIS UNIQUE STATE WAS CHARACTERIZED BY THE INCREASING EXPRESSION OF INHIBITORY CHECKPOINT RECEPTORS, AND INTERVENTIONS TARGETING IMMUNE CHECKPOINT BLOCKADES (ICBS) HAVE BEEN CONSIDERED AS A PROMISING STRATEGY TO STIMULATE T-CELL KILLING. RECENT INVESTIGATIONS HAVE DEMONSTRATED THAT EXHAUSTED T CELLS NOT ONLY DISPLAY FUNCTIONAL, METABOLIC, TRANSCRIPTIONAL, AND EPIGENETIC DIFFERENCES BUT ALSO COMPRISE A HETEROGENEOUS GROUP OF CELLS. IN THIS REVIEW, WE SUMMARIZE THE CURRENT FINDINGS ON DYNAMIC DIFFERENTIATION PROCESS DURING TEX HETEROGENEITY DEVELOPMENT IN CANCER AND CHRONIC INFECTION. WE DISCUSS HOW THE RESPONSES TO IMMUNOTHERAPY ARE DETERMINED BY THESE DISTINCT SUBSETS AND HIGHLIGHT PROSPECTIVE APPROACHES FOR IMPROVING THE EFFICACY OF ICB THERAPY FOR CANCER BY LEVERAGING THE HETEROGENEITY OF T CELLS. 2023 14 6365 37 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 15 6677 37 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 16 4434 27 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 17 1464 34 DISSECTING THE HETEROGENEITY OF EXHAUSTED T CELLS AT THE MOLECULAR LEVEL. OUR UNDERSTANDING OF MECHANISMS UNDERLYING T-CELL EXHAUSTION HAS BEEN REFINED BY ANALYSIS OF EXHAUSTED T CELLS AT THE MOLECULAR LEVEL. THE DEVELOPMENT AND FUNCTIONS OF EXHAUSTED T CELLS ARE REGULATED BY A NUMBER OF TRANSCRIPTION FACTORS, EPIGENETIC FACTORS AND METABOLIC ENZYMES. IN ADDITION, RECENT WORK TO DISSECT EXHAUSTED T CELLS AT THE SINGLE-CELL LEVEL HAS ENABLED US TO DISCOVER A PRECURSOR EXHAUSTED T-CELL SUBSET EQUIPPED WITH LONG-TERM SURVIVAL CAPACITY. STARTING FROM THE ANALYSIS OF MOUSE MODELS, THE EXISTENCE OF PRECURSOR EXHAUSTED T CELLS HAS ALSO BEEN DOCUMENTED IN HUMAN T CELLS IN THE CONTEXT OF CHRONIC VIRUS INFECTIONS OR TUMORS. CLINICAL DATA SUGGEST THAT EVALUATING THE QUALITY OF EXHAUSTED T CELLS ON THE BASIS OF THEIR DIFFERENTIATION STATUS MAY BE HELPFUL TO PREDICT THE THERAPEUTIC RESPONSE TO INHIBITION OF PROGRAMMED DEATH 1 (PD1). MOREOVER, BEYOND IMMUNE-CHECKPOINT BLOCKADE, NOVEL THERAPEUTIC APPROACHES TO RE-INVIGORATE EXHAUSTED T CELLS HAVE BEEN EXPLORED BASED ON MOLECULAR INSIGHTS INTO T-CELL EXHAUSTION. HERE I WILL DISCUSS KEY MOLECULAR PROFILES ASSOCIATED WITH THE DEVELOPMENT, MAINTENANCE AND DIFFERENTIATION OF EXHAUSTED T CELLS AND HOW THESE FINDINGS CAN BE APPLICABLE IN THE FIELD OF CANCER IMMUNOTHERAPY. 2022 18 6530 31 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 19 2367 29 EPIGENETIC REGULATION OF T CELL EXHAUSTION. CHRONIC ANTIGEN STIMULATION DURING VIRAL INFECTIONS AND CANCER CAN LEAD TO T CELL EXHAUSTION, WHICH IS CHARACTERIZED BY REDUCED EFFECTOR FUNCTION AND PROLIFERATION, AND THE EXPRESSION OF INHIBITORY IMMUNE CHECKPOINT RECEPTORS. RECENT STUDIES HAVE DEMONSTRATED THAT T CELL EXHAUSTION RESULTS IN WHOLESCALE EPIGENETIC REMODELING THAT CONFERS PHENOTYPIC STABILITY TO THESE CELLS AND PREVENTS T CELL REINVIGORATION BY CHECKPOINT BLOCKADE. HERE, WE REVIEW FOUNDATIONAL TECHNOLOGIES TO PROFILE THE EPIGENOME AT MULTIPLE SCALES, INCLUDING MAPPING THE LOCATIONS OF TRANSCRIPTION FACTORS AND HISTONE MODIFICATIONS, DNA METHYLATION AND THREE-DIMENSIONAL GENOME CONFORMATION. WE DISCUSS HOW THESE TECHNOLOGIES HAVE ELUCIDATED THE DEVELOPMENT AND EPIGENETIC REGULATION OF EXHAUSTED T CELLS AND FUNCTIONAL IMPLICATIONS ACROSS VIRAL INFECTION, CANCER, AUTOIMMUNITY AND ENGINEERED T CELL THERAPIES. FINALLY, WE COVER EMERGING MULTI-OMIC AND GENOME ENGINEERING TECHNOLOGIES, CURRENT AND UPCOMING OPPORTUNITIES TO APPLY THESE TO T CELL EXHAUSTION, AND THERAPEUTIC OPPORTUNITIES FOR T CELL ENGINEERING IN THE CLINIC. 2022 20 3895 34 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