1 770 82 CD8(+) T CELL DYSFUNCTION BY TOX INTOXICATION: A PROTUMORIGENIC EVENT IN THE TUMOR MICROENVIRONMENT. ACCUMULATING EVIDENCE SUGGESTS THE ROLE OF CELLULAR COMPONENTS IN ACHIEVING ANTITUMOR TO PROTUMOR MICROENVIRONMENTS. AMONG THE VARIOUS TYPES OF CELLS WITHIN THE TUMOR NICHE, THE STATE OF CD8(+) T CELLS APPARENTLY CHANGES FROM CYTOTOXIC T EFFECTOR CELLS AND MEMORY T CELLS TO EXHAUSTED CD8(+) T CELLS. THESE CHANGES IN THE PHENOTYPE OF CD8(+) T CELLS PROMOTE THE PROTUMOR MICROENVIRONMENT. RECENTLY, COMPREHENSIVE EXPERIMENTAL DATA DELINEATED THE ROLE OF THYMOCYTE SELECTION-ASSOCIATED HIGH-MOBILITY GROUP-BOX PROTEIN (TOX), WHICH REGULATES THE TRANSCRIPTIONAL PROCESS AND EPIGENETIC REMODELING, WITH IMPLICATIONS IN TUMOR AND CHRONIC VIRAL INFECTIONS. THIS PERSPECTIVE SUMMARIZES THE MOLECULAR MECHANISMS THAT LINK CD8(+) T CELLS, TOX, AND TRANSCRIPTIONAL AND EPIGENETIC REPROGRAMMING AS WELL AS FUTURE DIRECTIONS FOR DETERMINING NEW AVENUES OF CANCER THERAPEUTICS. 2021 2 5593 40 ROLE, FUNCTION AND REGULATION OF THE THYMOCYTE SELECTION-ASSOCIATED HIGH MOBILITY GROUP BOX PROTEIN IN CD8(+) T CELL EXHAUSTION. THYMOCYTE SELECTION-ASSOCIATED HIGH MOBILITY GROUP BOX PROTEIN (TOX), A MEMBER OF THE HIGH-MOTILITY GROUP BOX (HMG) PROTEIN SUPERFAMILY, IS AN EVOLUTIONARILY CONSERVED DNA-BINDING PROTEIN. IT FUNCTIONS AS A TRANSCRIPTION FACTOR THAT MODULATES TRANSCRIPTIONAL PROGRAMS BY BINDING TO DNA IN A STRUCTURE-DEPENDENT MANNER. IT HAS BEEN WELL ESTABLISHED THAT TOX IS REQUIRED FOR THE DEVELOPMENT OF CD4(+) T CELLS, NATURAL KILLER (NK) CELLS AND INNATE LYMPHOID CELLS (ILCS), AS WELL AS THE AUTOIMMUNITY MEDIATED BY CD8(+) T CELLS. RECENTLY, EMERGING EVIDENCE SUPPORTS AN ESSENTIAL ROLE FOR TOX IN THE INDUCTION OF T CELL EXHAUSTION IN THE SETTING OF TUMOR OR CHRONIC VIRAL INFECTION BY MEDIATING TRANSCRIPTIONAL AND EPIGENETIC CHANGES, WHICH ARE CARDINAL HALLMARKS OF EXHAUSTED T CELLS. MOREOVER, TOX PLAYS A KEY ROLE IN THE PERSISTENCE OF ANTIGEN-SPECIFIC T CELLS AND IN THE MITIGATION OF TISSUE DAMAGE CAUSED BY IMMUNOPATHOLOGY OVER THE COURSE OF TUMORIGENESIS AND CHRONIC INFECTION. ADDITIONALLY, TOX CONTRIBUTES TO THE HIGH LEVEL OF PROGRAMMED CELL DEATH PROTEIN 1 (PD-1) ON THE CELL SURFACE BY PARTICIPATING IN THE PROCESS OF ENDOCYTIC RECYCLING OF PD-1. IN THIS REVIEW, WE SUMMARIZE THE MOST RECENT INFORMATION ABOUT THE ROLE OF TOX IN THE PROCESS OF T CELL EXHAUSTION, WHICH ENRICHES OUR UNDERSTANDING OF THE MOLECULAR MECHANISMS OF CD8(+) T CELL EXHAUSTION UPON CHRONIC ANTIGEN STIMULATION AND REVEALS PROMISING THERAPEUTIC TARGETS FOR PERSISTING INFECTION AND CANCER. 2021 3 2718 33 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 4 6851 33 [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 5 4726 25 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 6 790 26 CELLULAR AND MOLECULAR MECHANISMS OF CD8(+) T CELL DIFFERENTIATION, DYSFUNCTION AND EXHAUSTION. T CELLS FOLLOW A TRIPHASIC DISTINCT PATHWAY OF ACTIVATION, PROLIFERATION AND DIFFERENTIATION BEFORE BECOMING FUNCTIONALLY AND PHENOTYPICALLY "EXHAUSTED" IN SETTINGS OF CHRONIC INFECTION, AUTOIMMUNITY AND IN CANCER. EXHAUSTED T CELLS PROGRESSIVELY LOSE CANONICAL EFFECTOR FUNCTIONS, EXHIBIT ALTERED TRANSCRIPTIONAL NETWORKS AND EPIGENETIC SIGNATURES AND GAIN CONSTITUTIVE EXPRESSION OF A BROAD COINHIBITORY RECEPTOR SUITE. THIS REVIEW OUTLINES RECENT ADVANCES IN OUR UNDERSTANDING OF EXHAUSTED T CELL BIOLOGY AND EXAMINES CELLULAR AND MOLECULAR MECHANISMS BY WHICH A STATE OF DYSFUNCTION OR EXHAUSTION IS ESTABLISHED, AND MECHANISMS BY WHICH EXHAUSTED T CELLS MAY STILL CONTRIBUTE TO PATHOGEN OR TUMOUR CONTROL. FURTHER, THIS REVIEW DESCRIBES OUR UNDERSTANDING OF EXHAUSTED T CELL HETEROGENEITY AND OUTLINES THE MECHANISMS BY WHICH CHECKPOINT BLOCKADE DIFFERENTIALLY ENGAGES EXHAUSTED T CELL SUBSETS TO OVERCOME EXHAUSTION AND RECOVER T CELL FUNCTION. 2020 7 2410 23 EPIGENETIC SCARS OF CD8(+) T CELL EXHAUSTION PERSIST AFTER CURE OF CHRONIC INFECTION IN HUMANS. T CELL EXHAUSTION IS AN INDUCED STATE OF DYSFUNCTION THAT ARISES IN RESPONSE TO CHRONIC INFECTION AND CANCER. EXHAUSTED CD8(+) T CELLS ACQUIRE A DISTINCT EPIGENETIC STATE, BUT IT IS NOT KNOWN WHETHER THAT CHROMATIN LANDSCAPE IS FIXED OR PLASTIC FOLLOWING THE RESOLUTION OF A CHRONIC INFECTION. HERE WE SHOW THAT THE EPIGENETIC STATE OF EXHAUSTION IS LARGELY IRREVERSIBLE, EVEN AFTER CURATIVE THERAPY. ANALYSIS OF CHROMATIN ACCESSIBILITY IN HCV- AND HIV-SPECIFIC RESPONSES IDENTIFIES A CORE EPIGENETIC PROGRAM OF EXHAUSTION IN CD8(+) T CELLS, WHICH UNDERGOES ONLY LIMITED REMODELING BEFORE AND AFTER RESOLUTION OF INFECTION. MOREOVER, CANONICAL FEATURES OF EXHAUSTION, INCLUDING SUPER-ENHANCERS NEAR THE GENES TOX AND HIF1A, REMAIN 'EPIGENETICALLY SCARRED.' T CELL EXHAUSTION IS THEREFORE A CONSERVED EPIGENETIC STATE THAT BECOMES FIXED AND PERSISTS INDEPENDENT OF CHRONIC ANTIGEN STIMULATION AND INFLAMMATION. THERAPEUTIC EFFORTS TO REVERSE T CELL EXHAUSTION MAY REQUIRE NEW APPROACHES THAT INCREASE THE EPIGENETIC PLASTICITY OF EXHAUSTED T CELLS. 2021 8 771 34 CD8(+) T CELL EXHAUSTION. CD8(+) T CELLS ARE IMPORTANT FOR THE PROTECTIVE IMMUNITY AGAINST INTRACELLULAR PATHOGENS AND TUMOR. IN THE CASE OF CHRONIC INFECTION OR CANCER, CD8(+) T CELLS ARE EXPOSED TO PERSISTENT ANTIGEN AND/OR INFLAMMATORY SIGNALS. THIS EXCESSIVE AMOUNT OF SIGNALS OFTEN LEADS CD8(+) T CELLS TO GRADUAL DETERIORATION OF T CELL FUNCTION, A STATE CALLED "EXHAUSTION." EXHAUSTED T CELLS ARE CHARACTERIZED BY PROGRESSIVE LOSS OF EFFECTOR FUNCTIONS (CYTOKINE PRODUCTION AND KILLING FUNCTION), EXPRESSION OF MULTIPLE INHIBITORY RECEPTORS (SUCH AS PD-1 AND LAG3), DYSREGULATED METABOLISM, POOR MEMORY RECALL RESPONSE, AND HOMEOSTATIC PROLIFERATION. THESE ALTERED FUNCTIONS ARE CLOSELY RELATED WITH ALTERED TRANSCRIPTIONAL PROGRAM AND EPIGENETIC LANDSCAPE THAT CLEARLY DISTINGUISH EXHAUSTED T CELLS FROM NORMAL EFFECTOR AND MEMORY T CELLS. T CELL EXHAUSTION IS OFTEN ASSOCIATED WITH INEFFICIENT CONTROL OF PERSISTING INFECTIONS AND CANCERS, BUT RE-INVIGORATION OF EXHAUSTED T CELLS WITH INHIBITORY RECEPTOR BLOCKADE CAN PROMOTE IMPROVED IMMUNITY AND DISEASE OUTCOME. ACCUMULATING EVIDENCES SUPPORT THE THERAPEUTIC POTENTIAL OF TARGETING EXHAUSTED T CELLS. HOWEVER, EXHAUSTED T CELLS COMPRISE HETEROGENOUS CELL POPULATION WITH DISTINCT RESPONSIVENESS TO INTERVENTION. UNDERSTANDING MOLECULAR MECHANISM OF T CELL EXHAUSTION IS ESSENTIAL TO ESTABLISH RATIONAL IMMUNOTHERAPEUTIC INTERVENTIONS. 2019 9 2879 32 FUNDAMENTALS TO THERAPEUTICS: EPIGENETIC MODULATION OF CD8(+) T CELL EXHAUSTION IN THE TUMOR MICROENVIRONMENT. IN THE SETTING OF CHRONIC ANTIGEN EXPOSURE IN THE TUMOR MICROENVIRONMENT (TME), CYTOTOXIC CD8(+) T CELLS (CTLS) LOSE THEIR IMMUNE SURVEILLANCE CAPABILITIES AND ABILITY TO CLEAR TUMOR CELLS AS A RESULT OF THEIR DIFFERENTIATION INTO TERMINALLY EXHAUSTED CD8(+) T CELLS. IMMUNE CHECKPOINT BLOCKADE (ICB) THERAPIES REINVIGORATE EXHAUSTED CD8(+) T CELLS BY TARGETING SPECIFIC INHIBITORY RECEPTORS, THUS PROMOTING THEIR CYTOLYTIC ACTIVITY TOWARDS TUMOR CELLS. DESPITE EXCITING RESULTS WITH ICB THERAPIES, MANY PATIENTS WITH SOLID TUMORS STILL FAIL TO RESPOND TO SUCH THERAPIES AND PATIENTS WHO INITIALLY RESPOND CAN DEVELOP RESISTANCE. RECENTLY, THROUGH NEW SEQUENCING TECHNOLOGIES SUCH AS THE ASSAY FOR TRANSPOSASE-ACCESSIBLE CHROMATIN WITH SEQUENCING (ATAC-SEQ), EPIGENETICS HAS BEEN APPRECIATED AS A CONTRIBUTING FACTOR THAT ENFORCES T CELL DIFFERENTIATION TOWARD EXHAUSTION IN THE TME. IMPORTANTLY, SPECIFIC EPIGENETIC ALTERATIONS AND EPIGENETIC FACTORS HAVE BEEN FOUND TO CONTROL CD8(+) T CELL EXHAUSTION PHENOTYPES. IN THIS REVIEW, WE WILL EXPLAIN THE BACKGROUND OF T CELL DIFFERENTIATION AND VARIOUS EXHAUSTION STATES AND DISCUSS HOW EPIGENETICS PLAY AN IMPORTANT ROLE IN THESE PROCESSES. THEN WE WILL OUTLINE SPECIFIC EPIGENETIC CHANGES AND CERTAIN EPIGENETIC AND TRANSCRIPTION FACTORS THAT ARE KNOWN TO CONTRIBUTE TO CD8(+) T CELL EXHAUSTION. WE WILL ALSO DISCUSS THE MOST RECENT METHODOLOGIES THAT ARE USED TO STUDY AND DISCOVER SUCH EPIGENETIC MODULATIONS. FINALLY, WE WILL EXPLAIN HOW EPIGENETIC REPROGRAMMING IS A PROMISING APPROACH THAT MIGHT FACILITATE THE DEVELOPMENT OF NOVEL EXHAUSTED T CELL-TARGETING IMMUNOTHERAPIES. 2022 10 5704 29 SINGLE-CELL RNA-SEQ REVEALS TOX AS A KEY REGULATOR OF CD8(+) T CELL PERSISTENCE IN CHRONIC INFECTION. PROGENITOR-LIKE CD8(+) T CELLS MEDIATE LONG-TERM IMMUNITY TO CHRONIC INFECTION AND CANCER AND RESPOND POTENTLY TO IMMUNE CHECKPOINT BLOCKADE. THESE CELLS SHARE TRANSCRIPTIONAL REGULATORS WITH MEMORY PRECURSOR CELLS, INCLUDING T CELL-SPECIFIC TRANSCRIPTION FACTOR 1 (TCF1), BUT IT IS UNCLEAR WHETHER THEY ADOPT DISTINCT PROGRAMS TO ADAPT TO THE IMMUNOSUPPRESSIVE ENVIRONMENT. BY COMPARING THE SINGLE-CELL TRANSCRIPTOMES AND EPIGENETIC PROFILES OF CD8(+) T CELLS RESPONDING TO ACUTE AND CHRONIC VIRAL INFECTIONS, WE FOUND THAT PROGENITOR-LIKE CD8(+) T CELLS BECAME DISTINCT FROM MEMORY PRECURSOR CELLS BEFORE THE PEAK OF THE T CELL RESPONSE. WE DISCOVERED A COEXPRESSION GENE MODULE CONTAINING TOX THAT EXHIBITED HIGHER TRANSCRIPTIONAL ACTIVITY ASSOCIATED WITH MORE ABUNDANT ACTIVE HISTONE MARKS IN PROGENITOR-LIKE CELLS THAN MEMORY PRECURSOR CELLS. MOREOVER, THYMOCYTE SELECTION-ASSOCIATED HIGH MOBILITY GROUP BOX PROTEIN TOX (TOX) PROMOTED THE PERSISTENCE OF ANTIVIRAL CD8(+) T CELLS AND WAS REQUIRED FOR THE PROGRAMMING OF PROGENITOR-LIKE CD8(+) T CELLS. THUS, LONG-TERM CD8(+) T CELL IMMUNITY TO CHRONIC VIRAL INFECTION REQUIRES UNIQUE TRANSCRIPTIONAL AND EPIGENETIC PROGRAMS ASSOCIATED WITH THE TRANSCRIPTION FACTOR TOX. 2019 11 6530 33 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 12 6060 30 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 13 2367 26 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 14 2145 25 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 15 5414 30 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 16 2056 25 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 17 4178 24 MEMORY T-CELL HETEROGENEITY AND TERMINOLOGY. IMMUNOLOGICAL MEMORY AND EXHAUSTION ARE FUNDAMENTAL FEATURES OF ADAPTIVE IMMUNITY. RECENT ADVANCES REVEAL INCREASING HETEROGENEITY AND DIVERSITY AMONG CD8 T-CELL SUBSETS, RESULTING IN NEW SUBSETS TO ANNOTATE AND UNDERSTAND. HERE, WE REVIEW OUR CURRENT KNOWLEDGE OF DIFFERENTIATION AND MAINTENANCE OF MEMORY AND EXHAUSTED CD8 T CELLS, INCLUDING PHENOTYPIC CLASSIFICATION, DEVELOPMENTAL PATHS, TRANSCRIPTIONAL AND EPIGENETIC FEATURES, AND CELL INTRINSIC AND EXTRINSIC FACTORS. ADDITIONALLY, WE USE THIS OUTLINE TO DISCUSS THE NOMENCLATURE OF EFFECTOR, MEMORY, AND EXHAUSTED CD8 T CELLS. FINALLY, WE DISCUSS HOW NEW FINDINGS ABOUT THESE CELL TYPES MAY IMPACT THE THERAPEUTIC EFFICACY AND DEVELOPMENT OF IMMUNOTHERAPIES TARGETING EFFECTOR, MEMORY, AND/OR EXHAUSTED CD8 T CELLS IN CHRONIC INFECTIONS AND CANCER. 2021 18 5248 26 PROGRAMMED CELL DEATH 1-DIRECTED IMMUNOTHERAPY FOR ENHANCING T-CELL FUNCTION. T-CELL EXHAUSTION IS A UNIQUE STATE THAT APPEARS DURING MANY CHRONIC INFECTIONS AND CANCER AND IS CHARACTERIZED BY LOSS OF PROLIFERATIVE CAPACITY AND EFFECTOR FUNCTION. COMPLEX MECHANISMS ARE INVOLVED IN THIS T-CELL DYSFUNCTION BUT AN INHIBITORY RECEPTOR, PD-1, HAS BEEN IDENTIFIED AS A MAJOR REGULATOR OF T-CELL EXHAUSTION. BLOCKADE OF THE PD-1 PATHWAY CAN REINVIGORATE EXHAUSTED T CELLS, RESULTING IN BETTER CONTROL OF CHRONIC INFECTIONS AND CANCER. NOTABLY, RECENT CLINICAL STUDIES HAVE REVEALED THAT PD-1-DIRECTED IMMUNOTHERAPY IS HIGHLY EFFECTIVE IN CANCER PATIENTS, DEMONSTRATING THAT PD-1 IS A PROMISING THERAPEUTIC TARGET IN HUMANS. IN THIS REVIEW, WE SUMMARIZE OUR CURRENT UNDERSTANDING OF THE EPIGENETIC REGULATION OF PD-1 EXPRESSION IN T CELLS AND DISCUSS POTENTIAL COMBINATION THERAPY WITH PD-1 BLOCKADE TOWARD DEVELOPING MORE EFFECTIVE TREATMENT FOR CHRONIC INFECTIONS AND CANCER. 2013 19 769 27 CD8 T CELL EXHAUSTION DURING CHRONIC VIRAL INFECTION AND CANCER. EXHAUSTED CD8 T (TEX) CELLS ARE A DISTINCT CELL LINEAGE THAT ARISE DURING CHRONIC INFECTIONS AND CANCERS IN ANIMAL MODELS AND HUMANS. TEX CELLS ARE CHARACTERIZED BY PROGRESSIVE LOSS OF EFFECTOR FUNCTIONS, HIGH AND SUSTAINED INHIBITORY RECEPTOR EXPRESSION, METABOLIC DYSREGULATION, POOR MEMORY RECALL AND HOMEOSTATIC SELF-RENEWAL, AND DISTINCT TRANSCRIPTIONAL AND EPIGENETIC PROGRAMS. THE ABILITY TO REINVIGORATE TEX CELLS THROUGH INHIBITORY RECEPTOR BLOCKADE, SUCH AS ALPHAPD-1, HIGHLIGHTS THE THERAPEUTIC POTENTIAL OF TARGETING THIS POPULATION. EMERGING INSIGHTS INTO THE MECHANISMS OF EXHAUSTION ARE INFORMING IMMUNOTHERAPIES FOR CANCER AND CHRONIC INFECTIONS. HOWEVER, LIKE OTHER IMMUNE CELLS, TEX CELLS ARE HETEROGENEOUS AND INCLUDE PROGENITOR AND TERMINAL SUBSETS WITH UNIQUE CHARACTERISTICS AND RESPONSES TO CHECKPOINT BLOCKADE. HERE, WE REVIEW OUR CURRENT UNDERSTANDING OF TEX CELL BIOLOGY, INCLUDING THE DEVELOPMENTAL PATHS, TRANSCRIPTIONAL AND EPIGENETIC FEATURES, AND CELL INTRINSIC AND EXTRINSIC FACTORS CONTRIBUTING TO EXHAUSTION AND HOW THIS KNOWLEDGE MAY INFORM THERAPEUTIC TARGETING OF TEX CELLS IN CHRONIC INFECTIONS, AUTOIMMUNITY, AND CANCER. 2019 20 2146 28 EPIGENETIC MANIPULATION RESTORES FUNCTIONS OF DEFECTIVE CD8(+) T CELLS FROM CHRONIC VIRAL INFECTION. FUNCTIONAL EXHAUSTION OF ANTIGEN-SPECIFIC T CELLS IS A DEFINING CHARACTERISTIC OF MANY CHRONIC INFECTIONS, BUT THE UNDERLYING MECHANISMS OF T CELL DYSFUNCTION ARE NOT WELL UNDERSTOOD. EPIGENETICS PLAYS AN IMPORTANT ROLE IN THE CONTROL OF T CELL DEVELOPMENT, DIFFERENTIATION, AND FUNCTION. TO EXAMINE IF EPIGENETICS ALSO PLAYS A ROLE IN T CELL EXHAUSTION, WE ANALYZED CHROMATIN REMODELING IN CD8(+) T CELLS FROM MICE WITH CHRONIC LYMPHOCYTIC CHORIOMENINGITIS VIRUS INFECTION. WE OBSERVED DOWNREGULATION OF DIACETYLATED HISTONE H3 IN BOTH VIRUS-SPECIFIC AND TOTAL CD8(+) T CELLS, AND FUNCTIONAL DEFECTS NOT ONLY IN VIRUS-SPECIFIC CD8(+) T CELLS BUT ALSO WITHIN THE TOTAL CD8(+) T CELL POPULATION. IN VITRO TREATMENT OF THESE EXHAUSTED CD8(+) T CELLS WITH HISTONE DEACETYLASE INHIBITORS RESTORED DIACETYLATED HISTONE H3 LEVELS, AND IMPROVED THEIR IMMUNE FUNCTIONS. UPON ADOPTIVE TRANSFER, THESE TREATED CD8(+) T CELLS DEVELOPED INTO FUNCTIONAL MEMORY T CELLS IN VIVO THAT ENHANCED PROTECTIVE IMMUNITY. THESE RESULTS DEFINE A ROLE OF EPIGENETICS IN T CELL EXHAUSTION AND SUGGEST EPIGENETIC MANIPULATION AS A NOVEL MOLECULAR THERAPY TO RESTORE IMMUNE FUNCTIONS. 2014