1 2878 160 FUNCTIONAL T CELLS ARE CAPABLE OF SUPERNUMERARY CELL DIVISION AND LONGEVITY. DIFFERENTIATED SOMATIC MAMMALIAN CELLS PUTATIVELY EXHIBIT SPECIES-SPECIFIC DIVISION LIMITS THAT IMPEDE CANCER BUT MAY CONSTRAIN LIFESPANS(1-3). TO PROVIDE IMMUNITY, TRANSIENTLY STIMULATED CD8(+) T CELLS UNDERGO UNUSUALLY RAPID BURSTS OF NUMEROUS CELL DIVISIONS, AND THEN FORM QUIESCENT LONG-LIVED MEMORY CELLS THAT REMAIN POISED TO REPROLIFERATE FOLLOWING SUBSEQUENT IMMUNOLOGICAL CHALLENGES. HERE WE ADDRESSED WHETHER T CELLS ARE INTRINSICALLY CONSTRAINED BY CHRONOLOGICAL OR CELL-DIVISION LIMITS. WE ACTIVATED MOUSE T CELLS IN VIVO USING ACUTE HETEROLOGOUS PRIME-BOOST-BOOST VACCINATIONS(4), TRANSFERRED EXPANDED CELLS TO NEW MICE, AND THEN REPEATED THIS PROCESS ITERATIVELY. OVER 10 YEARS (GREATLY EXCEEDING THE MOUSE LIFESPAN)(5) AND 51 SUCCESSIVE IMMUNIZATIONS, T CELLS REMAINED COMPETENT TO RESPOND TO VACCINATION. CELLS REQUIRED SUFFICIENT REST BETWEEN STIMULATION EVENTS. DESPITE DEMONSTRATING THE POTENTIAL TO EXPAND THE STARTING POPULATION AT LEAST 10(40)-FOLD, CELLS DID NOT SHOW LOSS OF PROLIFERATION CONTROL AND RESULTS WERE NOT DUE TO CONTAMINATION WITH YOUNG CELLS. PERSISTENT STIMULATION BY CHRONIC INFECTIONS OR CANCER CAN CAUSE T CELL PROLIFERATIVE SENESCENCE, FUNCTIONAL EXHAUSTION AND DEATH(6). WE FOUND THAT ALTHOUGH ITERATIVE ACUTE STIMULATIONS ALSO INDUCED SUSTAINED EXPRESSION AND EPIGENETIC REMODELLING OF COMMON EXHAUSTION MARKERS (INCLUDING PD1, WHICH IS ALSO KNOWN AS PDCD1, AND TOX) IN THE CELLS, THEY COULD STILL PROLIFERATE, EXECUTE ANTIMICROBIAL FUNCTIONS AND FORM QUIESCENT MEMORY CELLS. THESE OBSERVATIONS PROVIDE A MODEL TO BETTER UNDERSTAND MEMORY CELL DIFFERENTIATION, EXHAUSTION, CANCER AND AGEING, AND SHOW THAT FUNCTIONALLY COMPETENT T CELLS CAN RETAIN THE POTENTIAL FOR EXTRAORDINARY POPULATION EXPANSION AND LONGEVITY WELL BEYOND THEIR ORGANISMAL LIFESPAN. 2023 2 5895 19 T CELL EXHAUSTION: AN EPIGENETICALLY IMPRINTED PHENOTYPIC AND FUNCTIONAL MAKEOVER. A RECENT ARTICLE IN CELL DEMONSTRATES THAT THE ABSENCE OF A SINGLE DNA METHYLTRANSFERASE, DNMT3A, PREVENTS CYTOTOXIC T CELLS FROM ACQUIRING THE HYPOFUNCTIONAL OR EXHAUSTED PHENOTYPE TYPICALLY SEEN IN CHRONIC VIRAL INFECTIONS AND TUMORS. UPON ESTABLISHING A CAUSAL RELATIONSHIP BETWEEN EXHAUSTION-ASSOCIATED EPIGENETIC CHANGES AND REDUCED CD8(+) T CELL FUNCTION, THE AUTHORS PROVIDED MECHANISTIC EVIDENCE THAT EXHAUSTION CONSTITUTES A SPECIFIC DIFFERENTIATION PROGRAM. 2017 3 2718 34 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 5015 42 PERSISTENCE OF SELF-REACTIVE CD8+ T CELLS IN THE CNS REQUIRES TOX-DEPENDENT CHROMATIN REMODELING. SELF-REACTIVE CD8(+) T CELLS ARE IMPORTANT MEDIATORS OF PROGRESSIVE TISSUE DAMAGE IN AUTOIMMUNE DISEASES, BUT THE MOLECULAR PROGRAM UNDERLYING THESE CELLS' FUNCTIONAL ADAPTATION IS UNCLEAR. HERE WE CHARACTERIZE THE TRANSCRIPTIONAL AND EPIGENETIC LANDSCAPE OF SELF-REACTIVE CD8(+) T CELLS IN A MOUSE MODEL OF PROTRACTED CENTRAL NERVOUS SYSTEM (CNS) AUTOIMMUNITY AND COMPARE IT TO POPULATIONS OF CNS-RESIDENT MEMORY CD8(+) T CELLS EMERGING FROM ACUTE VIRAL INFECTION. WE FIND THAT AUTOIMMUNE CD8(+) T CELLS PERSISTING AT SITES OF SELF-ANTIGEN EXHIBIT CHARACTERISTIC TRANSCRIPTIONAL REGULATION TOGETHER WITH DISTINCT EPIGENETIC REMODELING. THIS SELF-REACTIVE CD8(+) T CELL FATE DEPENDS ON THE TRANSCRIPTIONAL REGULATION BY THE DNA-BINDING HMG-BOX PROTEIN TOX WHICH REMODELS MORE THAN 400 GENOMIC REGIONS INCLUDING LOCI SUCH AS TCF7, WHICH IS CENTRAL TO STEMNESS OF CD8(+) T CELLS. CONTINUOUS EXPOSURE TO CNS SELF-ANTIGEN SUSTAINS TOX LEVELS IN SELF-REACTIVE CD8(+) T CELLS, WHEREAS GENETIC ABLATION OF TOX IN CD8(+) T CELLS RESULTS IN SHORTENED PERSISTENCE OF SELF-REACTIVE CD8(+) T CELLS IN THE INFLAMED CNS. OUR STUDY ESTABLISHES AND CHARACTERIZES THE GENETIC DIFFERENTIATION PROGRAM ENABLING CHRONIC T CELL-DRIVEN IMMUNOPATHOLOGY IN CNS AUTOIMMUNITY. 2021 5 2410 34 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 6 6530 30 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 7 5248 34 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 8 5414 39 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 9 2146 37 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 10 4726 29 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 5901 26 T-CELL HETEROGENEITY, PROGENITOR-PROGENY RELATIONSHIPS, AND FUNCTION DURING LATENT AND CHRONIC VIRAL INFECTIONS. UPON RESOLUTION OF AN ACUTE VIRAL INFECTION, DURING LATENT-REACTIVATING INFECTION AND DURING CHRONIC ACTIVE INFECTIONS VIRUS-SPECIFIC T-CELLS DIFFERENTIATE INTO DISTINCT SUBSETS THAT DIFFER IN PHENOTYPE, LONGEVITY, TRANSCRIPTIONAL, METABOLIC, AND EPIGENETIC PROFILES, AND EFFECTOR FUNCTIONS. WITH RECENT ADVANCES IN SINGLE-CELL PROFILING, THIS SUBSTANTIAL HETEROGENEITY HAS BECOME APPARENT AND NEW SUBSETS OF VIRUS-SPECIFIC T CELLS, EITHER OF STABLE OR TRANSITORY NATURE, ARE BEING IDENTIFIED. A UNIFYING PRINCIPLE OF T CELLS EMERGING IN THESE DIFFERENT CONDITIONS IS THEIR PRECURSOR-PROGENY RELATIONSHIP. FOR ACUTE AND RESOLVED VIRAL INFECTIONS, THIS RELATIONSHIP BECOMES APPARENT DURING RE-CHALLENGE, WHEREAS A CONSTANT DIFFERENTIATION OF PROGENITOR T CELLS INTO MORE DIFFERENTIATED CELLS OCCURS DURING LATENT-REACTIVATING AND ACTIVE CHRONIC VIRAL INFECTIONS. IN THIS REVIEW, WE SUMMARIZE AND DISCUSS CURRENT KNOWLEDGE ABOUT T-CELL HETEROGENEITY AND PROGENITOR-PROGENY RELATIONSHIPS IN THE SETTING OF PERSISTENT VIRAL INFECTIONS. 2023 12 1763 39 EARLY TRANSCRIPTIONAL AND EPIGENETIC DIVERGENCE OF CD8+ T CELLS RESPONDING TO ACUTE VERSUS CHRONIC INFECTION. DURING A MICROBIAL INFECTION, RESPONDING CD8+ T CELLS GIVE RISE TO EFFECTOR CELLS THAT PROVIDE ACUTE HOST DEFENSE AND MEMORY CELLS THAT PROVIDE SUSTAINED PROTECTION. AN ALTERNATIVE OUTCOME IS EXHAUSTION, A STATE OF T CELL DYSFUNCTION THAT OCCURS IN THE CONTEXT OF CHRONIC INFECTIONS AND CANCER. ALTHOUGH IT IS EVIDENT THAT EXHAUSTED CD8+ T (TEX) CELLS ARE PHENOTYPICALLY AND MOLECULARLY DISTINCT FROM EFFECTOR AND MEMORY CD8+ T CELLS, THE FACTORS REGULATING THE EARLIEST EVENTS IN THE DIFFERENTIATION PROCESS OF TEX CELLS REMAIN INCOMPLETELY UNDERSTOOD. HERE, WE PERFORMED SINGLE-CELL RNA-SEQUENCING AND SINGLE-CELL ATAC-SEQUENCING OF CD8+ T CELLS RESPONDING TO LCMV-ARMSTRONG (LCMV-ARM) OR LCMV-CLONE 13 (LCMV-CL13), WHICH RESULT IN ACUTE OR CHRONIC INFECTIONS, RESPECTIVELY. COMPARED TO CD8+ T CELLS THAT HAD UNDERGONE THEIR FIRST DIVISION IN RESPONSE TO LCMV-ARM (DIV1ARM) CELLS, CD8+ T CELLS THAT HAD UNDERGONE THEIR FIRST DIVISION IN RESPONSE TO LCMV-CL13 (DIV1CL13) EXPRESSED HIGHER LEVELS OF GENES ENCODING TRANSCRIPTION FACTORS PREVIOUSLY ASSOCIATED WITH EXHAUSTION, ALONG WITH HIGHER LEVELS OF EZH2, THE CATALYTIC COMPONENT OF THE POLYCOMB REPRESSIVE COMPLEX 2 (PRC2) COMPLEX, WHICH MEDIATES EPIGENETIC SILENCING. MODULATION OF EZH2 RESULTED IN ALTERED EXPRESSION OF EXHAUSTION-ASSOCIATED MOLECULES BY CD8+ T CELLS RESPONDING TO LCMV-CL13, THOUGH THE SPECIFIC CELLULAR AND INFECTIOUS CONTEXTS, RATHER THAN SIMPLY THE LEVEL OF EZH2 EXPRESSION, LIKELY DETERMINE THE EVENTUAL OUTCOME. TAKEN TOGETHER, THESE FINDINGS SUGGEST THAT THE DIFFERENTIATION PATHS OF CD8+ T CELLS RESPONDING TO ACUTE VERSUS CHRONIC INFECTIONS MAY DIVERGE EARLIER THAN PREVIOUSLY APPRECIATED. 2023 13 198 34 ACQUIRED TRANSCRIPTIONAL PROGRAMMING IN FUNCTIONAL AND EXHAUSTED VIRUS-SPECIFIC CD8 T CELLS. PURPOSE OF REVIEW: FAILURE TO CONTROL VIRAL INFECTIONS SUCH AS HIV RESULTS IN T-CELL RECEPTOR (TCR) AND INHIBITORY RECEPTOR DRIVEN EXHAUSTION OF ANTIGEN-SPECIFIC T CELLS. PERSISTENT SIGNALING BY THESE RECEPTORS DURING CHRONIC VIRAL INFECTION SCULPTS THE TRANSCRIPTIONAL REGULATORY PROGRAMS OF VIRUS-SPECIFIC T CELLS. THE RESULTING GENE EXPRESSION PROFILE IS TAILORED TO TEMPER THE POTENTIALLY DAMAGING EFFECTOR FUNCTIONS OF CYTOTOXIC T CELLS AND ADAPT THEM TO AN ANTIGEN-RICH AND INFLAMMATION-RICH ENVIRONMENT. HERE WE REVIEW RECENT STUDIES INVESTIGATING MECHANISMS OF TRANSCRIPTIONAL REGULATION OF EFFECTOR, FUNCTIONAL MEMORY, AND EXHAUSTED T-CELL FUNCTIONS DURING ACUTE VERSUS CHRONIC INFECTIONS. RECENT FINDINGS: PATTERNS OF GENE EXPRESSION IN VIRUS-SPECIFIC CD8 T CELLS ARE A RESULT OF A COMBINATION OF PRO AND INHIBITORY SIGNALS FROM ANTIGEN PRESENTATION (TCR-MEDIATED) AND CO-INHIBITORY RECEPTOR LIGATION (PD-1, 2B4). FURTHER, MEMORY-SPECIFIC TRANSCRIPTIONAL REGULATION OF 2B4 EXPRESSION AND SIGNALING IMPOSE A SELF-LIMITING SECONDARY EFFECTOR RESPONSE TO A PROLONGED VIRAL INFECTION. ADDITIONALLY, DIFFERENTIATION OF FUNCTIONAL MEMORY CD8 T CELLS IS COUPLED WITH ACQUISITION OF A REPRESSIVE EPIGENETIC PROGRAM FOR PD-1 EXPRESSION. HOWEVER, CHRONIC INFECTION PROVIDES A SIGNAL THAT BLOCKS THE ACQUISITION OF THESE EPIGENETIC MODIFICATIONS REINFORCING THE SUPPRESSION OF CYTOTOXIC LYMPHOCYTE (CTL) FUNCTIONS IN EXHAUSTED CELLS. SUMMARY: CURRENT FINDINGS SUGGEST THAT THE MECHANISM(S) THAT DELINEATE FUNCTIONAL MEMORY VERSUS EXHAUSTION ARE COUPLED WITH ACQUISITION OF TRANSCRIPTIONAL PROGRAMS AT THE EFFECTOR STAGE OF DIFFERENTIATION, REINFORCED BY CESSATION OR PERSISTENCE OF TCR SIGNALING. 2012 14 5059 32 PHENOTYPIC AND IMMUNOMETABOLIC ASPECTS ON STEM CELL MEMORY AND RESIDENT MEMORY CD8(+) T CELLS. THE IMMUNE SYSTEM, SMARTLY AND SURPRISINGLY, SAVES THE EXPOSURE OF A PARTICULAR PATHOGEN IN ITS MEMORY AND REACTS TO THE PATHOGEN VERY RAPIDLY, PREVENTING SERIOUS DISEASES. IMMUNOLOGISTS HAVE LONG BEEN FASCINATED BY UNDERSTANDING THE ABILITY TO RECALL AND RESPOND FASTER AND MORE VIGOROUSLY TO A PATHOGEN, KNOWN AS "MEMORY". T-CELL POPULATIONS CAN BE BETTER DESCRIBED BY USING MORE SOPHISTICATED TECHNIQUES TO DEFINE PHENOTYPE, TRANSCRIPTIONAL AND EPIGENETIC SIGNATURES AND METABOLIC PATHWAYS (SINGLE-CELL RESOLUTION), WHICH UNCOVERED THE HETEROGENEITY OF THE MEMORY T-COMPARTMENT. PHENOTYPE, EFFECTOR FUNCTIONS, MAINTENANCE, AND METABOLIC PATHWAYS HELP IDENTIFY THESE DIFFERENT SUBSETS. HERE, WE EXAMINE RECENT DEVELOPMENTS IN THE CHARACTERIZATION OF THE HETEROGENEITY OF THE MEMORY T CELL COMPARTMENT. IN PARTICULAR, WE FOCUS ON THE EMERGING ROLE OF CD8(+) T(RM) AND T(SCM) CELLS, PROVIDING EVIDENCE ON HOW THEIR IMMUNOMETABOLISM OR MODULATION CAN PLAY A VITAL ROLE IN THEIR GENERATION AND MAINTENANCE IN CHRONIC CONDITIONS SUCH AS INFECTIONS OR AUTOIMMUNE DISEASES. 2022 15 3167 37 GROUP 1 METABOTROPIC GLUTAMATE RECEPTOR EXPRESSION DEFINES A T CELL MEMORY POPULATION DURING CHRONIC TOXOPLASMA INFECTION THAT ENHANCES IFN-GAMMA AND PERFORIN PRODUCTION IN THE CNS. WITHIN THE BRAIN, A PRO-INFLAMMATORY RESPONSE IS ESSENTIAL TO PREVENT CLINICAL DISEASE DUE TO TOXOPLASMA GONDII REACTIVATION. INFECTION IN THE IMMUNOCOMPROMISED LEADS TO LETHAL TOXOPLASMIC ENCEPHALITIS WHILE IN THE IMMUNOCOMPETENT, THERE IS PERSISTENT LOW-GRADE INFLAMMATION WHICH IS DEVOID OF CLINICAL SYMPTOMS. THIS SIGNIFIES THAT THERE IS A WELL-BALANCED AND REGULATED INFLAMMATORY RESPONSE TO T. GONDII IN THE BRAIN. T CELLS ARE THE DOMINANT IMMUNE CELLS THAT PREVENT CLINICAL DISEASE, AND THIS IS MEDIATED THROUGH THE SECRETION OF EFFECTOR MOLECULES SUCH AS PERFORINS AND IFN-GAMMA. THE PRESENCE OF COGNATE ANTIGEN, THE EXPRESSION OF SURVIVAL CYTOKINES, AND THE ALTERATION OF THE EPIGENETIC LANDSCAPE DRIVE THE DEVELOPMENT OF MEMORY T CELLS. HOWEVER, SPECIFIC EXTRINSIC SIGNALS THAT PROMOTE THE FORMATION AND MAINTENANCE OF MEMORY T CELLS WITHIN TISSUE ARE POORLY UNDERSTOOD. DURING CHRONIC INFECTION, THERE IS AN INCREASE IN EXTRACELLULAR GLUTAMATE THAT, DUE TO ITS FUNCTION AS AN EXCITATORY NEUROTRANSMITTER, IS NORMALLY TIGHTLY CONTROLLED IN THE CNS. HERE WE DEMONSTRATE THAT CD8(+) T CELLS FROM THE T. GONDII-INFECTED BRAIN PARENCHYMA ARE ENRICHED FOR METABOTROPIC GLUTAMATE RECEPTORS (MGLUR'S). CHARACTERIZATION STUDIES DETERMINED THAT MGLUR(+) EXPRESSION BY CD8(+) T CELLS DEFINES A DISTINCT MEMORY POPULATION AT THE TRANSCRIPTIONAL AND PROTEIN LEVEL. FINALLY, USING RECEPTOR ANTAGONISTS AND AGONISTS WE DEMONSTRATE MGLUR SIGNALING IS REQUIRED FOR OPTIMAL CD8(+) T CELL PRODUCTION OF THE EFFECTOR CYTOKINE IFNGAMMA. THIS WORK SUGGESTS THAT GLUTAMATE IS AN IMPORTANT ENVIRONMENTAL SIGNAL OF INFLAMMATION THAT PROMOTES T CELL FUNCTION. UNDERSTANDING GLUTAMATE'S INFLUENCE ON T CELLS IN THE BRAIN CAN PROVIDE INSIGHTS INTO THE MECHANISMS THAT GOVERN PROTECTIVE IMMUNITY AGAINST CNS-INFILTRATING PATHOGENS AND NEUROINFLAMMATION. 2023 16 2367 30 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 17 2056 38 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 18 6060 35 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 19 790 30 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 20 2446 23 EPIGENETIC STRATEGIES SYNERGIZE WITH PD-L1/PD-1 TARGETED CANCER IMMUNOTHERAPIES TO ENHANCE ANTITUMOR RESPONSES. IMMUNOTHERAPY STRATEGIES TARGETING THE PROGRAMMED CELL DEATH LIGAND 1 (PD-L1)/PROGRAMMED CELL DEATH 1 (PD-1) PATHWAY IN CLINICAL TREATMENTS HAVE ACHIEVED REMARKABLE SUCCESS IN TREATING MULTIPLE TYPES OF CANCER. HOWEVER, OWING TO THE HETEROGENEITY OF TUMORS AND INDIVIDUAL IMMUNE SYSTEMS, PD-L1/PD-1 BLOCKADE STILL SHOWS SLOW RESPONSE RATES IN CONTROLLING MALIGNANCIES IN MANY PATIENTS. ACCUMULATING EVIDENCE HAS SHOWN THAT AN EFFECTIVE RESPONSE TO ANTI-PD-L1/ANTI-PD-1 THERAPY REQUIRES ESTABLISHING AN INTEGRATED IMMUNE CYCLE. DAMAGE IN ANY STEP OF THE IMMUNE CYCLE IS ONE OF THE MOST IMPORTANT CAUSES OF IMMUNOTHERAPY FAILURE. IMPAIRMENTS IN THE IMMUNE CYCLE CAN BE RESTORED BY EPIGENETIC MODIFICATION, INCLUDING REPROGRAMMING THE ENVIRONMENT OF TUMOR-ASSOCIATED IMMUNITY, ELICITING AN IMMUNE RESPONSE BY INCREASING THE PRESENTATION OF TUMOR ANTIGENS, AND BY REGULATING T CELL TRAFFICKING AND REACTIVATION. THUS, A RATIONAL COMBINATION OF PD-L1/PD-1 BLOCKADE AND EPIGENETIC AGENTS MAY OFFER GREAT POTENTIAL TO RETRAIN THE IMMUNE SYSTEM AND TO IMPROVE CLINICAL OUTCOMES OF CHECKPOINT BLOCKADE THERAPY. 2020