1 3861 101 ISOLATION OF HUMAN ANTIGEN-SPECIFIC REGULATORY T CELLS WITH HIGH SUPPRESSIVE FUNCTION. ADOPTIVE TRANSFER OF REGULATORY T (TREG) CELLS COULD BE AN ALTERNATIVE TO CHRONIC IMMUNOSUPPRESSION FOR PREVENTION OF ALLOGENEIC GRAFT REJECTION. WHILE POLYSPECIFIC TREG CELLS CAN PREVENT IMMUNE RESPONSES UNDER LYMPHOPENIC CONDITIONS, AG-SPECIFIC TREG CELLS ARE NEEDED TO TREAT AUTOIMMUNITY AND GRAFT REJECTION. YET, RELIABLE MARKERS FOR AG-SPECIFIC TREG CELLS ARE MISSING. WE REPORT THAT LATENCY-ASSOCIATED PEPTIDE (LAP) AND GLYCOPROTEIN A REPETITIONS PREDOMINANT (GARP) CAN IDENTIFY HUMAN AG-SPECIFIC TREG CELLS. IN ADDITION, WE SHOW THAT THE DEPLETION OF CD154(+) CELLS FROM LAP(+) OR GARP(+) TREG CELLS INCREASES THE TREG-CELL PURITY TO OVER 90%, AS ASSESSED BY EPIGENETIC ANALYSIS. THESE AG-SPECIFIC TREG CELLS CAN BE ISOLATED MAGNETICALLY AND MIGHT CONTRIBUTE TO THE DEVELOPMENT OF GMP-BASED PROTOCOLS. IN ADDITION, AG-SPECIFIC TREG CELLS ARE FUNCTIONALLY FAR SUPERIOR TO CD4(+) CD25(HIGH) OR CD4(+) CD25(HIGH) CD127(LOW) TREG CELLS IN VITRO AND IN PREVENTING STRONG ALLOREACTIONS IN HUMANIZED MICE. THEY COULD, THEREFORE, HAVE A HIGH THERAPEUTIC POTENTIAL FOR THE CONTROL OF ALLOIMMUNE, AUTOIMMUNE, AND ALLERGIC IMMUNE RESPONSES IN PATIENTS. 2014 2 2959 23 GENETIC AND EPIGENETIC INSTABILITY INDUCED BY BETEL QUID ASSOCIATED CHEMICALS. OVER THE YEARS, BETEL QUID CHEWING AND TOBACCO USE HAVE ATTRACTED CONSIDERABLE INTEREST AS THEY ARE IMPLICATED AS THE MOST LIKELY CAUSATIVE RISK FACTORS OF ORAL AND ESOPHAGEAL CANCERS. ALTHOUGH ARECA NUT USE AND BETEL QUID CHEWING MAY LEAD TO APOPTOSIS, CHRONIC EXPOSURE TO ARECA NUT AND SLAKED LIME MAY PROMOTE PRE-MALIGNANT AND MALIGNANT TRANSFORMATION OF ORAL CELLS. THE PUTATIVE MUTAGENIC AND CARCINOGENIC MECHANISMS MAY INVOLVE ENDOGENOUS NITROSATION OF ARECA AND TOBACCO ALKALOIDS AS WELL AS THE PRESENCE OF DIRECT ALKYLATING AGENTS IN BETEL QUID AND SMOKELESS TOBACCO. METABOLIC ACTIVATION OF CARCINOGENIC N-NITROSAMINES BY PHASE-I ENZYMES IS REQUIRED NOT ONLY TO ELICIT THE GENOTOXICITY VIA THE REACTIVE INTERMEDIATES BUT ALSO TO POTENTIATE THE MUTAGENICITY WITH THE SPORADIC ALKYLATIONS OF NUCLEOTIDE BASES, RESULTING IN THE FORMATION OF DIVERSE DNA ADDUCTS. PERSISTENT DNA ADDUCTS PROVIDES THE IMPETUS FOR GENETIC AND EPIGENETIC LESIONS. THE GENETIC AND EPIGENETIC FACTORS CUMULATIVELY INFLUENCE THE DEVELOPMENT AND PROGRESSION OF DISORDERS SUCH AS CANCER. ACCUMULATION OF NUMEROUS GENETIC AND EPIGENETIC ABERRATIONS DUE TO LONG-TERM BETEL QUID (WITH OR WITHOUT TOBACCO) CHEWING AND TOBACCO USE CULMINATES INTO THE DEVELOPMENT OF HEAD AND NECK CANCERS. WE REVIEW RECENT EVIDENCE THAT SUPPORTS PUTATIVE MECHANISMS FOR MUTAGENICITY AND CARCINOGENICITY OF BETEL QUID CHEWING ALONG WITH TOBACCO (SMOKING AND SMOKELESS) USE. THE DETAILED MOLECULAR MECHANISMS OF THE EXTENT OF ACCUMULATION AND PATTERNS OF GENETIC ALTERATIONS, INDICATIVE OF THE PRIOR EXPOSURE TO CARCINOGENS AND ALKYLATING AGENTS BECAUSE OF BQ CHEWING AND TOBACCO USE, HAVE NOT YET BEEN ELUCIDATED. 2023 3 362 32 AMBIENT AIR POLLUTION IMPAIRS REGULATORY T-CELL FUNCTION IN ASTHMA. BACKGROUND: ASTHMA IS THE MOST FREQUENT CHRONIC DISEASE IN CHILDREN, AND CHILDREN ARE AT HIGH RISK FOR ADVERSE HEALTH CONSEQUENCES ASSOCIATED WITH AMBIENT AIR POLLUTION (AAP) EXPOSURE. REGULATORY T (TREG) CELLS ARE SUPPRESSORS OF IMMUNE RESPONSES INVOLVED IN ASTHMA PATHOGENESIS. TREG-CELL IMPAIRMENT IS ASSOCIATED WITH INCREASED DNA METHYLATION OF FORKHEAD BOX TRANSCRIPTION FACTOR 3 (FOXP3), A KEY TRANSCRIPTION FACTOR IN TREG-CELL ACTIVITY. BECAUSE AAP EXPOSURE CAN INDUCE EPIGENETIC CHANGES, WE HYPOTHESIZED THAT TREG-CELL FUNCTION WOULD BE IMPAIRED BY AAP, ALLOWING AMPLIFICATION OF AN INFLAMMATORY RESPONSE. OBJECTIVES: TO ASSESS WHETHER EXPOSURE TO AAP LED TO HYPERMETHYLATION OF THE FOXP3 GENE, CAUSING IMPAIRED TREG-CELL SUPPRESSION AND WORSENED ASTHMA SYMPTOM SCORES. METHODS: CHILDREN WITH AND WITHOUT ASTHMA FROM FRESNO, CALIF (HIGH POLLUTION, FRESNO ASTHMA GROUP [FA], N = 71, AND FRESNO NON ASTHMATIC GROUP, N = 30, RESPECTIVELY), AND FROM STANFORD, CALIF (LOW POLLUTION, STANFORD ASTHMA GROUP, N = 40, AND STANFORD NON ASTHMATIC GROUP, N = 40), WERE ENROLLED IN A CROSS-SECTIONAL STUDY. PERIPHERAL BLOOD TREG CELLS WERE USED IN FUNCTIONAL AND EPIGENETIC STUDIES. ASTHMA OUTCOMES WERE ASSESSED BY GLOBAL INITIATIVE IN ASTHMA SCORE. RESULTS: FRESNO ASTHMA GROUP TREG-CELL SUPPRESSION WAS IMPAIRED AND FA TREG-CELL CHEMOTAXIS WERE REDUCED COMPARED WITH OTHER GROUPS (P T) AND BRCA2 (C.6952C>T) AND SPLICING OF KDM6A (C.1194+2T>G), SUGGEST THAT THE DEVELOPMENT OF ESCC IN THE PATIENT WAS TRIGGERED BY IMPAIRMENT OF CHECKPOINT AND REPAIR FOR DNA DAMAGE AND EPIGENETIC MODIFICATION THROUGH ACCUMULATION OF GENE MUTATIONS INDUCED BY CHRONIC GRAFT-VERSUS-HOST DISEASE AND PROLONGED ADMINISTRATION OF TACROLIMUS. 2020 12 3845 12 IS AGING A "RETRO"SPECTIVE EVENT? REACTIVATION OF ENDOGENOUS RETROVIRUSES (ERVS), THE RELICS OF ANCIENT INFECTIONS, HAS BEEN IMPLICATED IN A NUMBER OF DISEASE CONTEXTS. IN THIS ISSUE OF CELL, LIU ET AL. SHOW HOW REACTIVATION OF ERVS IN OLD AGE CAN INDUCE SENESCENCE. THIS AWAKENING OF ERVS IS ASSOCIATED WITH THEIR EPIGENETIC DEREPRESSION AND CONTRIBUTES TO AGE-ASSOCIATED CHRONIC INFLAMMATION. 2023 13 4201 24 METABOLIC REWIRING AND REDOX ALTERATIONS IN MALIGNANT PLEURAL MESOTHELIOMA. MALIGNANT PLEURAL MESOTHELIOMA (MPM) IS A RARE MALIGNANCY OF MESOTHELIAL CELLS WITH INCREASING INCIDENCE, AND IN MANY CASES, DISMAL PROGNOSIS DUE TO ITS AGGRESSIVENESS AND LACK OF EFFECTIVE THERAPIES. ENVIRONMENTAL AND OCCUPATIONAL EXPOSURE TO ASBESTOS IS CONSIDERED THE MAIN AETIOLOGICAL FACTOR FOR MPM. INHALED ASBESTOS FIBRES ACCUMULATE IN THE LUNGS AND INDUCE THE GENERATION OF REACTIVE OXYGEN SPECIES (ROS) DUE TO THE PRESENCE OF IRON ASSOCIATED WITH THE FIBROUS SILICATES AND TO THE ACTIVATION OF MACROPHAGES AND INFLAMMATION. CHRONIC INFLAMMATION AND A ROS-ENRICHED MICROENVIRONMENT CAN FOSTER THE MALIGNANT TRANSFORMATION OF MESOTHELIAL CELLS. IN ADDITION, MPM CELLS HAVE A HIGHLY GLYCOLYTIC METABOLIC PROFILE AND ARE POSITIVE IN (18)F-FDG PET ANALYSIS. LOSS-OF-FUNCTION MUTATIONS OF BRCA-ASSOCIATED PROTEIN 1 (BAP1) ARE A MAJOR CONTRIBUTOR TO THE METABOLIC REWIRING OF MPM CELLS. A SUBSET OF MPM TUMOURS SHOW LOSS OF THE METHYLADENOSINE PHOSPHORYLASE (MTAP) LOCUS, RESULTING IN PROFOUND ALTERATIONS IN POLYAMINE METABOLISM, ATP AND METHIONINE SALVAGE PATHWAYS, AS WELL AS CHANGES IN EPIGENETIC CONTROL OF GENE EXPRESSION. THIS REVIEW PROVIDES AN OVERVIEW OF THE PERTURBATIONS IN METABOLISM AND ROS HOMOEOSTASIS OF MPM CELLS AND THE ROLE OF THESE ALTERATIONS IN MALIGNANT TRANSFORMATION AND TUMOUR PROGRESSION. 2020 14 407 32 ANALYSIS OF FOXP3+ REGULATORY T CELLS THAT DISPLAY APPARENT VIRAL ANTIGEN SPECIFICITY DURING CHRONIC HEPATITIS C VIRUS INFECTION. WE REPORTED PREVIOUSLY THAT A PROPORTION OF NATURAL CD25(+) CELLS ISOLATED FROM THE PBMC OF HCV PATIENTS CAN FURTHER UPREGULATE CD25 EXPRESSION IN RESPONSE TO HCV PEPTIDE STIMULATION IN VITRO, AND PROPOSED THAT VIRUS-SPECIFIC REGULATORY T CELLS (TREG) WERE PRIMED AND EXPANDED DURING THE DISEASE. HERE WE DESCRIBE EPIGENETIC ANALYSIS OF THE FOXP3 LOCUS IN HCV-RESPONSIVE NATURAL CD25(+) CELLS AND SHOW THAT THESE CELLS ARE NOT ACTIVATED CONVENTIONAL T CELLS EXPRESSING FOXP3, BUT HARD-WIRED TREG WITH A STABLE FOXP3 PHENOTYPE AND FUNCTION. OF APPROXIMATELY 46,000 GENES ANALYZED IN GENOME WIDE TRANSCRIPTION PROFILING, ABOUT 1% WERE DIFFERENTIALLY EXPRESSED BETWEEN HCV-RESPONSIVE TREG, HCV-NON-RESPONSIVE NATURAL CD25(+) CELLS AND CONVENTIONAL T CELLS. EXPRESSION PROFILES, INCLUDING CELL DEATH, ACTIVATION, PROLIFERATION AND TRANSCRIPTIONAL REGULATION, SUGGEST A SURVIVAL ADVANTAGE OF HCV-RESPONSIVE TREG OVER THE OTHER CELL POPULATIONS. SINCE NO TREG-SPECIFIC ACTIVATION MARKER IS KNOWN, WE TESTED 97 NS3-DERIVED PEPTIDES FOR THEIR ABILITY TO ELICIT CD25 RESPONSE (ASSUMING IT IS A SURROGATE MARKER), ACCOMPANIED BY HIGH RESOLUTION HLA TYPING OF THE PATIENTS. SOME REACTIVE PEPTIDES OVERLAPPED WITH PREVIOUSLY DESCRIBED EFFECTOR T CELL EPITOPES. OUR DATA OFFERS NEW INSIGHTS INTO HCV IMMUNE EVASION AND TOLERANCE, AND HIGHLIGHTS THE NON-SELF SPECIFIC NATURE OF TREG DURING INFECTION. 2009 15 3716 30 INHIBITING INFLAMMATION WITH MYELOID CELL-SPECIFIC NANOBIOLOGICS PROMOTES ORGAN TRANSPLANT ACCEPTANCE. INDUCING GRAFT ACCEPTANCE WITHOUT CHRONIC IMMUNOSUPPRESSION REMAINS AN ELUSIVE GOAL IN ORGAN TRANSPLANTATION. USING AN EXPERIMENTAL TRANSPLANTATION MOUSE MODEL, WE DEMONSTRATE THAT LOCAL MACROPHAGE ACTIVATION THROUGH DECTIN-1 AND TOLL-LIKE RECEPTOR 4 (TLR4) DRIVES TRAINED IMMUNITY-ASSOCIATED CYTOKINE PRODUCTION DURING ALLOGRAFT REJECTION. WE CONDUCTED NANOIMMUNOTHERAPEUTIC STUDIES AND FOUND THAT A SHORT-TERM MTOR-SPECIFIC HIGH-DENSITY LIPOPROTEIN (HDL) NANOBIOLOGIC TREATMENT (MTORI-HDL) AVERTED MACROPHAGE AEROBIC GLYCOLYSIS AND THE EPIGENETIC MODIFICATIONS UNDERLYING INFLAMMATORY CYTOKINE PRODUCTION. THE RESULTING REGULATORY MACROPHAGES PREVENTED ALLOREACTIVE CD8(+) T CELL-MEDIATED IMMUNITY AND PROMOTED TOLEROGENIC CD4(+) REGULATORY T (TREG) CELL EXPANSION. TO ENHANCE THERAPEUTIC EFFICACY, WE COMPLEMENTED THE MTORI-HDL TREATMENT WITH A CD40-TRAF6-SPECIFIC NANOBIOLOGIC (TRAF6I-HDL) THAT INHIBITS CO-STIMULATION. THIS SYNERGISTIC NANOIMMUNOTHERAPY RESULTED IN INDEFINITE ALLOGRAFT SURVIVAL. TOGETHER, WE SHOW THAT HDL-BASED NANOIMMUNOTHERAPY CAN BE EMPLOYED TO CONTROL MACROPHAGE FUNCTION IN VIVO. OUR STRATEGY, FOCUSED ON PREVENTING INFLAMMATORY INNATE IMMUNE RESPONSES, PROVIDES A FRAMEWORK FOR DEVELOPING TARGETED THERAPIES THAT PROMOTE IMMUNOLOGICAL TOLERANCE. 2018 16 559 20 BACH2 ENFORCES THE TRANSCRIPTIONAL AND EPIGENETIC PROGRAMS OF STEM-LIKE CD8(+) T CELLS. DURING CHRONIC INFECTION AND CANCER, A SELF-RENEWING CD8(+) T CELL SUBSET MAINTAINS LONG-TERM IMMUNITY AND IS CRITICAL TO THE EFFECTIVENESS OF IMMUNOTHERAPY. THESE STEM-LIKE CD8(+) T CELLS DIVERGE FROM OTHER CD8(+) SUBSETS EARLY AFTER CHRONIC VIRAL INFECTION. HOWEVER, PATHWAYS GUARDING STEM-LIKE CD8(+) T CELLS AGAINST TERMINAL EXHAUSTION REMAIN UNCLEAR. HERE, WE SHOW THAT THE GENE ENCODING TRANSCRIPTIONAL REPRESSOR BACH2 IS TRANSCRIPTIONALLY AND EPIGENETICALLY ACTIVE IN STEM-LIKE CD8(+) T CELLS BUT NOT TERMINALLY EXHAUSTED CELLS EARLY AFTER INFECTION. BACH2 OVEREXPRESSION ENFORCED STEM-LIKE CELL FATE, WHEREAS BACH2 DEFICIENCY IMPAIRED STEM-LIKE CD8(+) T CELL DIFFERENTIATION. SINGLE-CELL TRANSCRIPTOMIC AND EPIGENOMIC APPROACHES REVEALED THAT BACH2 ESTABLISHED THE TRANSCRIPTIONAL AND EPIGENETIC PROGRAMS OF STEM-LIKE CD8(+) T CELLS. IN ADDITION, BACH2 SUPPRESSED THE MOLECULAR PROGRAM DRIVING TERMINAL EXHAUSTION THROUGH TRANSCRIPTIONAL REPRESSION AND EPIGENETIC SILENCING. THUS, OUR STUDY REVEALS A NEW PATHWAY THAT ENFORCES COMMITMENT TO STEM-LIKE CD8(+) LINEAGE AND PREVENTS AN ALTERNATIVE TERMINALLY EXHAUSTED CELL FATE. 2021 17 5249 30 PROGRAMMED CELL DEATH-1 PATHWAY INHIBITION IN MYELOID MALIGNANCIES: IMPLICATIONS FOR MYELOPROLIFERATIVE NEOPLASMS. MYELOPROLIFERATIVE NEOPLASMS (MPNS) ARE CLONAL HEMATOPOIETIC DISEASES THAT BELONG TO THE SPECTRUM OF MYELOID MALIGNANCIES (MYMS), WHICH ALSO INCLUDE MYELODYSPLASTIC SYNDROMES (MDS), ACUTE MYELOID LEUKEMIA (AML), AND CHRONIC MYELOGENOUS LEUKEMIA (CML). WHILE HEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT) IS A POTENTIALLY CURATIVE THERAPEUTIC APPROACH TO MANY MYMS, THE ASSOCIATED MORBIDITY AND MORTALITY HAVE NECESSITATED THE DEVELOPMENT OF NON-HSCT THERAPEUTICS FOR SYMPTOM MANAGEMENT AND DISEASE COURSE MODIFICATION. IMMUNE CHECKPOINT INHIBITION, IN PARTICULAR ALONG THE PROGRAMMED CELL DEATH PROTEIN 1 (PD-1)/B7-H1 (PD-L1) AXIS, IS AN ESTABLISHED STRATEGY IN SOLID TUMORS WITH POTENTIAL AS AN ADJUNCTIVE THERAPY IN HEMATOLOGIC MALIGNANCIES. SEMINAL STUDIES SUGGEST THAT THE PRO-INFLAMMATORY MICROENVIRONMENT OF MYMS CAN SUPPRESS T LYMPHOCYTE-MEDIATED IMMUNITY VIA PD-1 SIGNALING AND THAT RESPONSE TO MAINSTAY EPIGENETIC THERAPIES FOR MYMS MAY BE GOVERNED BY PD-1 GENE REGULATION. ALTHOUGH THE ROLE OF PD-1 SIGNALING IN MPN PATHOGENESIS AND PROGRESSION IS AS YET UNCLEAR, RESEARCH IN MPN PATIENTS HAS REVEALED EXPANSION OF MYELOID-DERIVED SUPPRESSOR CELLS (MDSCS), WHICH MAY EFFECT HOST IMMUNE TOLERANCE OF TUMOR VIA TEMPORALLY AND SPATIALLY SPECIFIC ACTIVATION OF PD-1/PD-L1 SIGNALING. THE CURRENT UNDERSTANDING OF IMMUNE DYSFUNCTION IN MPNS AND ANALOGOUS MYMS OFFERS A COMPELLING RATIONALE TO STUDY PD-1/PD-L1 INHIBITION IN PATIENTS AS A NOVEL TREATMENT OPTION. 2017 18 1775 21 EBV IN T-/NK-CELL TUMORIGENESIS. EPSTEIN-BARR VIRUS (EBV), WHICH IS ASSOCIATED WITH B-CELL PROLIFERATIVE DISORDERS, ALSO TRANSFORMS T- OR NATURAL KILLER (NK)-LINEAGE CELLS AND HAS BEEN CONNECTED WITH VARIOUS T- OR NK (T/NK)-CELL MALIGNANCIES, SUCH AS EXTRANODAL NK/T-CELL LYMPHOMA-NASAL TYPE AND AGGRESSIVE NK-CELL LEUKEMIA. CHRONIC ACTIVE EBV (CAEBV) DISEASE , WHICH OCCURS MOST OFTEN IN CHILDREN AND YOUNG ADULTS IN EAST ASIA, IS AN EBV-ASSOCIATED T-/NK-CELL LYMPHOPROLIFERATIVE DISEASE. PATIENTS WITH CAEBV OFTEN PROGRESS TO OVERT LYMPHOMA OR LEUKEMIA OVER A LONG-TERM CLINICAL COURSE. EBV'S TRANSFORMING CAPACITY IN B CELLS IS WELL CHARACTERIZED, BUT THE MOLECULAR PATHOGENESIS OF CLONAL EXPANSION CAUSED BY EBV IN T/NK CELLS HAS NOT YET BEEN CLARIFIED. IN THE PRIMARY INFECTION, EBV INFECTS B CELLS AND EPITHELIAL CELLS AND MAY ALSO INFECT SOME T/NK CELLS. IN SOME INDIVIDUALS, BECAUSE OF POOR PRESENTATION BY SPECIFIC HUMAN LEUKOCYTE ANTIGENS OR THE GENETIC BACKGROUND, EBV-INFECTED T/NK CELLS EVADE HOST IMMUNITY AND SURVIVE. OCCASIONALLY, WITH THE HELP OF VIRAL ONCOGENES, EBV-ASSOCIATED T/NK LYMPHOPROLIFERATIVE DISEASES, SUCH AS CAEBV, MAY DEVELOP. THE SUBSEQUENT ACCUMULATION OF GENETIC MUTATIONS AND/OR EPIGENETIC MODIFICATIONS IN DRIVER GENES, SUCH AS DDX3X AND TP53, MAY LEAD TO OVERT LYMPHOMA AND LEUKEMIA. ACTIVATION-INDUCED CYTIDINE DEAMINASE AND THE APOBEC3 FAMILY, DRIVEN BY EBV INFECTION, MAY INDUCE CHROMOSOMAL RECOMBINATION AND SOMATIC MUTATIONS. 2018 19 5358 23 REBALANCING TGFBETA1/BMP SIGNALS IN EXHAUSTED T CELLS UNLOCKS RESPONSIVENESS TO IMMUNE CHECKPOINT BLOCKADE THERAPY. T CELL DYSFUNCTIONALITY PREVENTS THE CLEARANCE OF CHRONIC INFECTIONS AND CANCER. FURTHERMORE, EPIGENETIC PROGRAMMING IN DYSFUNCTIONAL CD8(+) T CELLS LIMITS THEIR RESPONSE TO IMMUNOTHERAPIES, INCLUDING IMMUNE CHECKPOINT BLOCKADE (ICB). HOWEVER, IT IS UNCLEAR WHICH UPSTREAM SIGNALS DRIVE ACQUISITION OF DYSFUNCTIONAL EPIGENETIC PROGRAMS, AND WHETHER THERAPEUTICALLY TARGETING THESE SIGNALS CAN REMODEL TERMINALLY DYSFUNCTIONAL T CELLS TO AN ICB-RESPONSIVE STATE. HERE WE INNOVATE AN IN VITRO MODEL SYSTEM OF STABLE HUMAN T CELL DYSFUNCTION AND SHOW THAT CHRONIC TGFBETA1 SIGNALING IN POSTEFFECTOR CD8(+) T CELLS ACCELERATES THEIR TERMINAL DYSFUNCTION THROUGH STABLE EPIGENETIC CHANGES. CONVERSELY, BOOSTING BONE MORPHOGENETIC PROTEIN (BMP) SIGNALING WHILE BLOCKING TGFBETA1 PRESERVED EFFECTOR AND MEMORY PROGRAMS IN CHRONICALLY STIMULATED HUMAN CD8(+) T CELLS, INDUCING SUPERIOR RESPONSES TO TUMORS AND SYNERGIZING THE ICB RESPONSES DURING CHRONIC VIRAL INFECTION. THUS, REBALANCING TGFBETA1/BMP SIGNALS PROVIDES AN EXCITING NEW APPROACH TO UNLEASH DYSFUNCTIONAL CD8(+) T CELLS AND ENHANCE T CELL IMMUNOTHERAPIES. 2023 20 1278 24 DE NOVO EPIGENETIC PROGRAMS INHIBIT PD-1 BLOCKADE-MEDIATED T CELL REJUVENATION. IMMUNE-CHECKPOINT-BLOCKADE (ICB)-MEDIATED REJUVENATION OF EXHAUSTED T CELLS HAS EMERGED AS A PROMISING APPROACH FOR TREATING VARIOUS CANCERS AND CHRONIC INFECTIONS. HOWEVER, T CELLS THAT BECOME FULLY EXHAUSTED DURING PROLONGED ANTIGEN EXPOSURE REMAIN REFRACTORY TO ICB-MEDIATED REJUVENATION. WE REPORT THAT BLOCKING DE NOVO DNA METHYLATION IN ACTIVATED CD8 T CELLS ALLOWS THEM TO RETAIN THEIR EFFECTOR FUNCTIONS DESPITE CHRONIC STIMULATION DURING A PERSISTENT VIRAL INFECTION. WHOLE-GENOME BISULFITE SEQUENCING OF ANTIGEN-SPECIFIC MURINE CD8 T CELLS AT THE EFFECTOR AND EXHAUSTION STAGES OF AN IMMUNE RESPONSE IDENTIFIED PROGRESSIVELY ACQUIRED HERITABLE DE NOVO METHYLATION PROGRAMS THAT RESTRICT T CELL EXPANSION AND CLONAL DIVERSITY DURING PD-1 BLOCKADE TREATMENT. MOREOVER, THESE EXHAUSTION-ASSOCIATED DNA-METHYLATION PROGRAMS WERE ACQUIRED IN TUMOR-INFILTRATING PD-1HI CD8 T CELLS, AND APPROACHES TO REVERSE THESE PROGRAMS IMPROVED T CELL RESPONSES AND TUMOR CONTROL DURING ICB. THESE DATA ESTABLISH DE NOVO DNA-METHYLATION PROGRAMMING AS A REGULATOR OF T CELL EXHAUSTION AND BARRIER OF ICB-MEDIATED T CELL REJUVENATION. 2017