1 4057 99 MAPPING THE LINEAGE RELATIONSHIP BETWEEN CXCR5(+) AND CXCR5(-) CD4(+) T CELLS IN HIV-INFECTED HUMAN LYMPH NODES. CXCR5 IS A KEY MARKER OF FOLLICULAR HELPER T (T(FH)) CELLS. USING PRIMARY LYMPH NODES (LNS) FROM HIV-INFECTED PATIENTS, WE IDENTIFIED A POPULATION OF CXCR5(-) CD4(+) T CELLS WITH T(FH)-CELL-LIKE FEATURES. THIS CXCR5(-) SUBSET BECOMES EXPANDED IN SEVERE HIV INFECTION AND IS CHARACTERIZED BY THE UPREGULATION OF ACTIVATION MARKERS AND HIGH PD-1 AND ICOS SURFACE EXPRESSION. INTEGRATED ANALYSES ON THE PHENOTYPIC HETEROGENEITY, FUNCTIONAL CAPACITY, T CELL RECEPTOR (TCR) REPERTOIRE, TRANSCRIPTIONAL PROFILE, AND EPIGENETIC STATE OF CXCR5(-)PD-1(+)ICOS(+) T CELLS REVEALED A SHARED CLONAL RELATIONSHIP WITH T(FH) CELLS. CXCR5(-)PD-1(+)ICOS(+) T CELLS RETAINED A POISED STATE FOR CXCR5 EXPRESSION AND EXHIBITED A MIGRATORY TRANSCRIPTIONAL PROGRAM. TCR SEQUENCE OVERLAP REVEALED A CONTRIBUTION OF LN-DERIVED CXCR5(-)PD-1(+)ICOS(+) T CELLS TO CIRCULATING CXCR5(-) CD4(+) T CELLS WITH B CELL HELP FUNCTION. THESE DATA LINK LN PATHOLOGY TO CIRCULATING T CELLS AND EXPAND THE CURRENT UNDERSTANDING ON THE DIVERSITY OF T CELLS THAT REGULATE B CELL RESPONSES DURING CHRONIC INFLAMMATION. 2019 2 5905 26 TACKLING THE HETEROGENEITY OF CVID. PURPOSE OF REVIEW: COMMON VARIABLE IMMUNODEFICIENCY IS CLINICALLY THE MOST RELEVANT PRIMARY IMMUNODEFICIENCY OF THE ADULT. ITS HETEROGENEITY HAS HINDERED PROGRESS IN THE PATHOGENETIC UNDERSTANDING OF THE MAJORITY OF COMMON VARIABLE IMMUNODEFICIENCY PATIENTS. THIS ABSTRACT SUMMARIZES RECENT ASPECTS OF THE FIELD AND EMPHASIZES THE NEED FOR A COMMONLY ACCEPTED APPROACH TO CLASSIFY COMMON VARIABLE IMMUNODEFICIENCY. RECENT FINDINGS: IN THE LAST 2 YEARS, THE FIRST GENETIC DEFECTS UNDERLYING COMMON VARIABLE IMMUNODEFICIENCY, INCLUDING ICOS, TACI, BAFF-R AND CD19, HAVE BEEN IDENTIFIED. THE ANALYSIS OF DENDRITIC CELLS DEMONSTRATED ALTERATIONS IN A MAJORITY OF PATIENTS IN ADDITION TO THE DISTURBED T AND B-CELL FUNCTION. SEVERAL CHANGES OF THE ADAPTIVE IMMUNE SYSTEM MIGHT BE SECONDARY TO AN UNDERLYING CHRONIC INFLAMMATORY SETTING POSSIBLY DUE TO A HHV8 INFECTION IN A SUBGROUP OF PATIENTS WITH GRANULOMATOUS DISEASE, AUTOIMMUNE PHENOMENA AND T-CELL DYSFUNCTION. THE OCCURRENCE OF GRANULOMATOUS INFLAMMATION IS ASSOCIATED WITH A WORSE PROGNOSIS COMPARED WITH COMMON VARIABLE IMMUNODEFICIENCY PATIENTS WITHOUT GRANULOMA. SUMMARY: THE PATHOGENESIS OF COMMON VARIABLE IMMUNODEFICIENCY INCLUDES DISTURBANCES OF THE ADAPTIVE AS WELL AS INNATE IMMUNE SYSTEM. IDENTIFIED MONOGENIC DEFECTS ACCOUNT FOR ABOUT 10% OF CASES, LEAVING THE MAJORITY OF DEFECTS UNDEFINED AND CERTAINLY IN PART EPIGENETIC. TO COMBINE THE KNOWN ASPECTS OF THE PATHOGENESIS OF COMMON VARIABLE IMMUNODEFICIENCY TO A CONCLUSIVE PICTURE, THE CLINICAL AND IMMUNOLOGIC PHENOTYPING OF PATIENTS NEEDS TO BE STANDARDIZED. 2005 3 5853 29 SUBSETS OF EXHAUSTED CD8(+) T CELLS DIFFERENTIALLY MEDIATE TUMOR CONTROL AND RESPOND TO CHECKPOINT BLOCKADE. T CELL DYSFUNCTION IS A HALLMARK OF MANY CANCERS, BUT THE BASIS FOR T CELL DYSFUNCTION AND THE MECHANISMS BY WHICH ANTIBODY BLOCKADE OF THE INHIBITORY RECEPTOR PD-1 (ANTI-PD-1) REINVIGORATES T CELLS ARE NOT FULLY UNDERSTOOD. HERE WE SHOW THAT SUCH THERAPY ACTS ON A SPECIFIC SUBPOPULATION OF EXHAUSTED CD8(+) TUMOR-INFILTRATING LYMPHOCYTES (TILS). DYSFUNCTIONAL CD8(+) TILS POSSESS CANONICAL EPIGENETIC AND TRANSCRIPTIONAL FEATURES OF EXHAUSTION THAT MIRROR THOSE SEEN IN CHRONIC VIRAL INFECTION. EXHAUSTED CD8(+) TILS INCLUDE A SUBPOPULATION OF 'PROGENITOR EXHAUSTED' CELLS THAT RETAIN POLYFUNCTIONALITY, PERSIST LONG TERM AND DIFFERENTIATE INTO 'TERMINALLY EXHAUSTED' TILS. CONSEQUENTLY, PROGENITOR EXHAUSTED CD8(+) TILS ARE BETTER ABLE TO CONTROL TUMOR GROWTH THAN ARE TERMINALLY EXHAUSTED T CELLS. PROGENITOR EXHAUSTED TILS CAN RESPOND TO ANTI-PD-1 THERAPY, BUT TERMINALLY EXHAUSTED TILS CANNOT. PATIENTS WITH MELANOMA WHO HAVE A HIGHER PERCENTAGE OF PROGENITOR EXHAUSTED CELLS EXPERIENCE A LONGER DURATION OF RESPONSE TO CHECKPOINT-BLOCKADE THERAPY. THUS, APPROACHES TO EXPAND THE POPULATION OF PROGENITOR EXHAUSTED CD8(+) T CELLS MIGHT BE AN IMPORTANT COMPONENT OF IMPROVING THE RESPONSE TO CHECKPOINT BLOCKADE. 2019 4 3281 34 HETEROGENEOUS TFH CELL POPULATIONS THAT DEVELOP DURING ENTERIC HELMINTH INFECTION PREDICT THE QUALITY OF TYPE 2 PROTECTIVE RESPONSE. T FOLLICULAR HELPER (TFH) CELLS ARE AN IMPORTANT COMPONENT OF GERMINAL CENTER (GC)-MEDIATED HUMORAL IMMUNITY. YET, HOW A CHRONIC TYPE 1 VERSUS PROTECTIVE TYPE 2 HELMINTH INFECTION MODULATES TFH-GC RESPONSES REMAINS POORLY UNDERSTOOD. HERE, WE EMPLOY THE HELMINTH TRICHURIS MURIS MODEL AND DEMONSTRATE THAT TFH CELL PHENOTYPES AND GC ARE DIFFERENTIALLY REGULATED IN ACUTE VERSUS CHRONIC INFECTION. THE LATTER FAILED TO INDUCE TFH-GC B CELL RESPONSES, WITH TFH CELLS EXPRESSING TAU-BET AND INTERFERON-GAMMA. IN CONTRAST, INTERLEUKIN-4-PRODUCING TFH CELLS DOMINATE RESPONSES TO AN ACUTE, RESOLVING INFECTION. HEIGHTENED EXPRESSION AND INCREASED CHROMATIN ACCESSIBILITY OF T HELPER (TH)1- AND TH2 CELL-ASSOCIATED GENES ARE OBSERVED IN CHRONIC AND ACUTE INDUCED TFH CELLS, RESPECTIVELY. BLOCKADE OF THE TH1 CELL RESPONSE BY T-CELL-INTRINSIC T-BET DELETION PROMOTED TFH CELL EXPANSION DURING CHRONIC INFECTION, POINTING TO A CORRELATION BETWEEN A ROBUST TFH CELL RESPONSE AND PROTECTIVE IMMUNITY TO PARASITES. FINALLY, BLOCKADE OF TFH-GC INTERACTIONS IMPAIRED TYPE 2 IMMUNITY, REVEALING THE CRITICAL PROTECTIVE ROLE OF GC-DEPENDENT TH2-LIKE TFH CELL RESPONSES DURING ACUTE INFECTION. COLLECTIVELY, THESE RESULTS PROVIDE NEW INSIGHTS INTO THE PROTECTIVE ROLES OF TFH-GC RESPONSES AND IDENTIFY DISTINCT TRANSCRIPTIONAL AND EPIGENETIC FEATURES OF TFH CELLS THAT EMERGE DURING RESOLVING OR CHRONIC T. MURIS INFECTION. 2023 5 2443 26 EPIGENETIC STABILITY OF EXHAUSTED T CELLS LIMITS DURABILITY OF REINVIGORATION BY PD-1 BLOCKADE. BLOCKING PROGRAMMED DEATH-1 (PD-1) CAN REINVIGORATE EXHAUSTED CD8 T CELLS (T(EX)) AND IMPROVE CONTROL OF CHRONIC INFECTIONS AND CANCER. HOWEVER, WHETHER BLOCKING PD-1 CAN REPROGRAM T(EX) INTO DURABLE MEMORY T CELLS (T(MEM)) IS UNCLEAR. WE FOUND THAT REINVIGORATION OF T(EX) IN MICE BY PD-L1 BLOCKADE CAUSED MINIMAL MEMORY DEVELOPMENT. AFTER BLOCKADE, REINVIGORATED T(EX) BECAME REEXHAUSTED IF ANTIGEN CONCENTRATION REMAINED HIGH AND FAILED TO BECOME T(MEM) UPON ANTIGEN CLEARANCE. T(EX) ACQUIRED AN EPIGENETIC PROFILE DISTINCT FROM THAT OF EFFECTOR T CELLS (T(EFF)) AND T(MEM) CELLS THAT WAS MINIMALLY REMODELED AFTER PD-L1 BLOCKADE. THIS FINDING SUGGESTS THAT T(EX) ARE A DISTINCT LINEAGE OF CD8 T CELLS. NEVERTHELESS, PD-1 PATHWAY BLOCKADE RESULTED IN TRANSCRIPTIONAL REWIRING AND REENGAGEMENT OF EFFECTOR CIRCUITRY IN THE T(EX) EPIGENETIC LANDSCAPE. THESE DATA INDICATE THAT EPIGENETIC FATE INFLEXIBILITY MAY LIMIT CURRENT IMMUNOTHERAPIES. 2016 6 833 14 CHARTING A SHARED EPIGENETIC PATHWAY TO CD8(+) T CELL DYSFUNCTION IN INFECTION AND CANCER. PRITYKIN ET AL. (2021) ESTABLISH A COMPREHENSIVE CHROMATIN ATLAS OF CD8(+) T CELL DYSFUNCTION IN CHRONIC VIRAL INFECTION AND CANCER VIA ANALYSIS OF BULK AND SINGLE-CELL ATAC-SEQ DATASETS ACROSS IMMUNE CHALLENGES. THESE RESULTS UNIFY THE CLASSIFICATION SCHEME AND MOLECULAR PROGRAMS DRIVING CD8(+) T CELL DYSFUNCTION ACROSS DISEASE SETTINGS AND WILL FACILITATE BASIC DISCOVERY AND TRANSLATIONAL EFFORTS IN T CELL IMMUNITY. 2021 7 568 26 BATF REGULATES PROGENITOR TO CYTOLYTIC EFFECTOR CD8(+) T CELL TRANSITION DURING CHRONIC VIRAL INFECTION. DURING CHRONIC VIRAL INFECTION, CD8(+) T CELLS DEVELOP INTO THREE MAJOR PHENOTYPICALLY AND FUNCTIONALLY DISTINCT SUBSETS: LY108(+)TCF-1(+) PROGENITORS, LY108(-)CX(3)CR1(-) TERMINALLY EXHAUSTED CELLS AND THE RECENTLY IDENTIFIED CX(3)CR1(+) CYTOTOXIC EFFECTOR CELLS. NEVERTHELESS, HOW CX(3)CR1(+) EFFECTOR CELL DIFFERENTIATION IS TRANSCRIPTIONALLY AND EPIGENETICALLY REGULATED REMAINS ELUSIVE. HERE, WE IDENTIFY DISTINCT GENE REGULATORY NETWORKS AND EPIGENETIC LANDSCAPES UNDERPINNING THE FORMATION OF THESE SUBSETS. NOTABLY, OUR DATA DEMONSTRATE THAT CX(3)CR1(+) EFFECTOR CELLS BEAR A STRIKING SIMILARITY TO SHORT-LIVED EFFECTOR CELLS DURING ACUTE INFECTION. GENETIC DELETION OF TBX21 SIGNIFICANTLY DIMINISHED FORMATION OF THE CX(3)CR1(+) SUBSET. IMPORTANTLY, WE FURTHER IDENTIFY A PREVIOUSLY UNAPPRECIATED ROLE FOR THE TRANSCRIPTION FACTOR BATF IN MAINTAINING A PERMISSIVE CHROMATIN STRUCTURE THAT ALLOWS THE TRANSITION FROM TCF-1(+) PROGENITORS TO CX(3)CR1(+) EFFECTOR CELLS. BATF DIRECTLY BOUND TO REGULATORY REGIONS NEAR TBX21 AND KLF2, MODULATING THEIR ENHANCER ACCESSIBILITY TO FACILITATE THE TRANSITION. THESE MECHANISTIC INSIGHTS CAN POTENTIALLY BE HARNESSED TO OVERCOME T CELL EXHAUSTION DURING CHRONIC INFECTION AND CANCER. 2021 8 6186 35 THE IMPACT OF HIV INFECTION ON THE FREQUENCIES, FUNCTION, SPATIAL LOCALIZATION AND HETEROGENEITY OF T FOLLICULAR REGULATORY CELLS (TFRS) WITHIN HUMAN LYMPH NODES. BACKGROUND: HIV ERADICATION EFFORTS HAVE BEEN UNSUCCESSFUL PARTLY DUE TO VIRUS PERSISTENCE IN IMMUNE SANCTUARY SITES SUCH AS GERMINAL CENTRES WITHIN LYMPH NODE (LN) TISSUES. RECENT EVIDENCE SUGGESTS THAT LNS HARBOUR A NOVEL SUBSET OF REGULATORY T CELLS, TERMED FOLLICULAR REGULATORY T CELLS (TFRS), BUT THEIR ROLE IN HIV PATHOGENESIS IS NOT FULLY ELUCIDATED. RESULTS: PAIRED EXCISIONAL LN AND PERIPHERAL BLOOD SAMPLES OBTAINED FROM 20 HIV-UNINFECTED AND 31 HIV-INFECTED TREATED AND 7 CHRONIC UNTREATED, WERE USED TO DETERMINE IF AND HOW HIV INFECTION MODULATE FREQUENCIES, FUNCTION AND SPATIAL LOCALIZATION OF TFRS WITHIN LN TISSUES. IMAGING STUDIES SHOWED THAT MOST TFRS ARE LOCALIZED IN EXTRA-FOLLICULAR REGIONS. CO-CULTURE ASSAYS SHOWED TFRS SUPPRESSION OF TFH HELP TO B CELLS. IMPORTANTLY, EPIGENETIC AND TRANSCRIPTIONAL STUDIES IDENTIFIED DPP4 AND FCRL3 AS NOVEL PHENOTYPIC MARKERS THAT DEFINE FOUR FUNCTIONALLY DISTINCT TFR SUBPOPULATIONS IN HUMAN LNS REGARDLESS OF HIV STATUS. IMAGING STUDIES CONFIRMED THE REGULATORY PHENOTYPE OF DPP4(+)TFRS. CONCLUSION: TOGETHER THESE STUDIES DESCRIBE TFRS DYNAMIC CHANGES DURING HIV INFECTION AND REVEAL PREVIOUSLY UNDERAPPRECIATED TFR HETEROGENEITY WITHIN HUMAN LNS. 2022 9 1262 33 CUTTING EDGE: PROLONGED EXPOSURE TO HIV REINFORCES A POISED EPIGENETIC PROGRAM FOR PD-1 EXPRESSION IN VIRUS-SPECIFIC CD8 T CELLS. AG-SPECIFIC CD8 T CELLS PLAY A CRITICAL ROLE IN CONTROLLING HIV INFECTION BUT EVENTUALLY LOSE ANTIVIRAL FUNCTIONS IN PART BECAUSE OF EXPRESSION AND SIGNALING THROUGH THE INHIBITORY PROGRAMMED DEATH-1 (PD-1) RECEPTOR. TO BETTER UNDERSTAND THE IMPACT OF PROLONGED TCR LIGATION ON REGULATION OF PD-1 EXPRESSION IN HIV-SPECIFIC CD8 T CELLS, WE INVESTIGATED THE CAPACITY OF VIRUS-SPECIFIC CD8 T CELLS TO MODIFY THE PD-1 EPIGENETIC PROGRAM AFTER REDUCTION IN VIRAL LOAD. WE OBSERVED THAT THE TRANSCRIPTIONAL REGULATORY REGION WAS UNMETHYLATED IN THE PD-1(HI) HIV-SPECIFIC CD8 T CELLS, WHEREAS IT REMAINED METHYLATED IN DONOR-MATCHED NAIVE CELLS AT ACUTE AND CHRONIC STAGES OF INFECTION. SURPRISINGLY, THE PD-1 PROMOTER REMAINED UNMETHYLATED IN HIV-SPECIFIC CD8 T CELLS FROM SUBJECTS WITH A VIRAL LOAD CONTROLLED BY ANTIVIRAL THERAPY FOR >2 Y OR FROM ELITE CONTROLLERS. TOGETHER, THESE DATA DEMONSTRATE THAT THE EPIGENETIC PROGRAM AT THE PD-1 LOCUS BECOMES FIXED AFTER PROLONGED EXPOSURE TO HIV VIRUS. 2013 10 1278 27 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 11 6482 28 TOX TRANSCRIPTIONALLY AND EPIGENETICALLY PROGRAMS CD8(+) T CELL EXHAUSTION. EXHAUSTED CD8(+) T (T(EX)) CELLS IN CHRONIC INFECTIONS AND CANCER HAVE LIMITED EFFECTOR FUNCTION, HIGH CO-EXPRESSION OF INHIBITORY RECEPTORS AND EXTENSIVE TRANSCRIPTIONAL CHANGES COMPARED WITH EFFECTOR (T(EFF)) OR MEMORY (T(MEM)) CD8(+) T CELLS. T(EX) CELLS ARE IMPORTANT CLINICAL TARGETS OF CHECKPOINT BLOCKADE AND OTHER IMMUNOTHERAPIES. EPIGENETICALLY, T(EX) CELLS ARE A DISTINCT IMMUNE SUBSET, WITH A UNIQUE CHROMATIN LANDSCAPE COMPARED WITH T(EFF) AND T(MEM) CELLS. HOWEVER, THE MECHANISMS THAT GOVERN THE TRANSCRIPTIONAL AND EPIGENETIC DEVELOPMENT OF T(EX) CELLS REMAIN UNKNOWN. HERE WE IDENTIFY THE HMG-BOX TRANSCRIPTION FACTOR TOX AS A CENTRAL REGULATOR OF T(EX) CELLS IN MICE. TOX IS LARGELY DISPENSABLE FOR THE FORMATION OF T(EFF) AND T(MEM) CELLS, BUT IT IS CRITICAL FOR EXHAUSTION: IN THE ABSENCE OF TOX, T(EX) CELLS DO NOT FORM. TOX IS INDUCED BY CALCINEURIN AND NFAT2, AND OPERATES IN A FEED-FORWARD LOOP IN WHICH IT BECOMES CALCINEURIN-INDEPENDENT AND SUSTAINED IN T(EX) CELLS. ROBUST EXPRESSION OF TOX THEREFORE RESULTS IN COMMITMENT TO T(EX) CELLS BY TRANSLATING PERSISTENT STIMULATION INTO A DISTINCT T(EX) CELL TRANSCRIPTIONAL AND EPIGENETIC DEVELOPMENTAL PROGRAM. 2019 12 1379 27 DEVELOPMENTAL RELATIONSHIPS OF FOUR EXHAUSTED CD8(+) T CELL SUBSETS REVEALS UNDERLYING TRANSCRIPTIONAL AND EPIGENETIC LANDSCAPE CONTROL MECHANISMS. CD8(+) T CELL EXHAUSTION IS A MAJOR BARRIER TO CURRENT ANTI-CANCER IMMUNOTHERAPIES. DESPITE THIS, THE DEVELOPMENTAL BIOLOGY OF EXHAUSTED CD8(+) T CELLS (TEX) REMAINS POORLY DEFINED, RESTRAINING IMPROVEMENT OF STRATEGIES AIMED AT "RE-INVIGORATING" TEX CELLS. HERE, WE DEFINED A FOUR-CELL-STAGE DEVELOPMENTAL FRAMEWORK FOR TEX CELLS. TWO TCF1(+) PROGENITOR SUBSETS WERE IDENTIFIED, ONE TISSUE RESTRICTED AND QUIESCENT AND ONE MORE BLOOD ACCESSIBLE, THAT GRADUALLY LOST TCF1 AS IT DIVIDED AND CONVERTED TO A THIRD INTERMEDIATE TEX SUBSET. THIS INTERMEDIATE SUBSET RE-ENGAGED SOME EFFECTOR BIOLOGY AND INCREASED UPON PD-L1 BLOCKADE BUT ULTIMATELY CONVERTED INTO A FOURTH, TERMINALLY EXHAUSTED SUBSET. BY USING TRANSCRIPTIONAL AND EPIGENETIC ANALYSES, WE IDENTIFIED THE CONTROL MECHANISMS UNDERLYING SUBSET TRANSITIONS AND DEFINED A KEY INTERPLAY BETWEEN TCF1, T-BET, AND TOX IN THE PROCESS. THESE DATA REVEAL A FOUR-STAGE DEVELOPMENTAL HIERARCHY FOR TEX CELLS AND DEFINE THE MOLECULAR, TRANSCRIPTIONAL, AND EPIGENETIC MECHANISMS THAT COULD PROVIDE OPPORTUNITIES TO IMPROVE CANCER IMMUNOTHERAPY. 2020 13 4178 21 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 14 3861 29 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 15 2421 29 EPIGENETIC SIGNATURE OF PD-1+ TCF1+ CD8 T CELLS THAT ACT AS RESOURCE CELLS DURING CHRONIC VIRAL INFECTION AND RESPOND TO PD-1 BLOCKADE. WE HAVE RECENTLY DEFINED A NOVEL POPULATION OF PD-1 (PROGRAMMED CELL DEATH 1)+ TCF1 (T CELL FACTOR 1)+ VIRUS-SPECIFIC CD8 T CELLS THAT FUNCTION AS RESOURCE CELLS DURING CHRONIC LCMV INFECTION AND PROVIDE THE PROLIFERATIVE BURST SEEN AFTER PD-1 BLOCKADE. SUCH CD8 T CELLS HAVE BEEN FOUND IN OTHER CHRONIC INFECTIONS AND ALSO IN CANCER IN MICE AND HUMANS. THESE CD8 T CELLS EXHIBIT STEM-LIKE PROPERTIES UNDERGOING SELF-RENEWAL AND ALSO DIFFERENTIATING INTO THE TERMINALLY EXHAUSTED CD8 T CELLS. HERE WE COMPARED THE EPIGENETIC SIGNATURE OF STEM-LIKE CD8 T CELLS WITH EXHAUSTED CD8 T CELLS. ATAC-SEQ ANALYSIS SHOWED THAT STEM-LIKE CD8 T CELLS HAD A UNIQUE SIGNATURE IMPLICATING ACTIVITY OF HMG (TCF) AND RHD (NF-KAPPAB) TRANSCRIPTION FACTOR FAMILY MEMBERS IN CONTRAST TO HIGHER ACCESSIBILITY TO ETS AND RUNX MOTIFS IN EXHAUSTED CD8 T CELLS. IN ADDITION, REGULATORY REGIONS OF THE TRANSCRIPTION FACTORS TCF7 AND ID3 WERE MORE ACCESSIBLE IN STEM-LIKE CELLS WHEREAS PRDM1 AND ID2 WERE MORE ACCESSIBLE IN EXHAUSTED CD8 T CELLS. WE ALSO COMPARED THE EPIGENETIC SIGNATURES OF THE 2 CD8 T CELL SUBSETS FROM CHRONICALLY INFECTED MICE WITH EFFECTOR AND MEMORY CD8 T CELLS GENERATED AFTER AN ACUTE LCMV INFECTION. BOTH CD8 T CELL SUBSETS GENERATED DURING CHRONIC INFECTION WERE STRIKINGLY DIFFERENT FROM CD8 T CELL SUBSETS FROM ACUTE INFECTION. INTERESTINGLY, THE STEM-LIKE CD8 T CELL SUBSET FROM CHRONIC INFECTION, DESPITE SHARING KEY FUNCTIONAL PROPERTIES WITH MEMORY CD8 T CELLS, HAD A VERY DISTINCT EPIGENETIC PROGRAM. THESE RESULTS SHOW THAT THE CHRONIC STEM-LIKE CD8 T CELL PROGRAM REPRESENTS A SPECIFIC ADAPTATION OF THE T CELL RESPONSE TO PERSISTENT ANTIGENIC STIMULATION. 2019 16 6481 32 TOX IS EXPRESSED BY EXHAUSTED AND POLYFUNCTIONAL HUMAN EFFECTOR MEMORY CD8(+) T CELLS. CD8(+) T CELL EXHAUSTION IS A HALLMARK OF MANY CANCERS AND CHRONIC INFECTIONS. IN MICE, T CELL FACTOR 1 (TCF-1) MAINTAINS EXHAUSTED CD8(+) T CELL RESPONSES, WHEREAS THYMOCYTE SELECTION-ASSOCIATED HMG BOX (TOX) IS REQUIRED FOR THE EPIGENETIC REMODELING AND SURVIVAL OF EXHAUSTED CD8(+) T CELLS. HOWEVER, IT HAS REMAINED UNCLEAR TO WHAT EXTENT THESE TRANSCRIPTION FACTORS PLAY ANALOGOUS ROLES IN HUMANS. IN THIS STUDY, WE MAPPED THE EXPRESSION OF TOX AND TCF-1 AS A FUNCTION OF DIFFERENTIATION AND SPECIFICITY IN THE HUMAN CD8(+) T CELL LANDSCAPE. HERE, WE DEMONSTRATE THAT CIRCULATING TOX(+) CD8(+) T CELLS EXIST IN MOST HUMANS, BUT THAT TOX IS NOT EXCLUSIVELY ASSOCIATED WITH EXHAUSTION. EFFECTOR MEMORY CD8(+) T CELLS GENERALLY EXPRESSED TOX, WHEREAS NAIVE AND EARLY-DIFFERENTIATED MEMORY CD8(+) T CELLS GENERALLY EXPRESSED TCF-1. CYTOLYTIC GENE AND PROTEIN EXPRESSION SIGNATURES WERE ALSO DEFINED BY THE EXPRESSION OF TOX. IN THE CONTEXT OF A RELENTLESS IMMUNE CHALLENGE, EXHAUSTED HIV-SPECIFIC CD8(+) T CELLS COMMONLY EXPRESSED TOX, OFTEN IN CLUSTERS WITH VARIOUS ACTIVATION MARKERS AND INHIBITORY RECEPTORS, AND EXPRESSED LESS TCF-1. HOWEVER, POLYFUNCTIONAL MEMORY CD8(+) T CELLS SPECIFIC FOR CYTOMEGALOVIRUS (CMV) OR EPSTEIN-BARR VIRUS (EBV) ALSO EXPRESSED TOX, EITHER WITH OR WITHOUT TCF-1. A SIMILAR PHENOTYPE WAS OBSERVED AMONG HIV-SPECIFIC CD8(+) T CELLS FROM INDIVIDUALS WHO MAINTAINED EXCEPTIONAL IMMUNE CONTROL OF VIRAL REPLICATION. COLLECTIVELY, THESE DATA DEMONSTRATE THAT TOX IS EXPRESSED BY MOST CIRCULATING EFFECTOR MEMORY CD8(+) T CELL SUBSETS AND NOT EXCLUSIVELY LINKED TO EXHAUSTION. 2020 17 5806 28 STRATEGIES TO REINVIGORATE EXHAUSTED CD8(+) T CELLS IN TUMOR MICROENVIRONMENT. CD8(+) T CELL EXHAUSTION IS A STABLE DYSFUNCTIONAL STATE DRIVEN BY CHRONIC ANTIGEN STIMULATION IN THE TUMOR MICROENVIRONMENT (TME). DIFFERENTIATION OF EXHAUSTED CD8(+) T CELLS (CD8(+) TEXS) IS ACCOMPANIED BY EXTENSIVE TRANSCRIPTIONAL, EPIGENETIC AND METABOLIC REPROGRAMMING. CD8(+) TEXS ARE MAINLY CHARACTERIZED BY IMPAIRED PROLIFERATIVE AND CYTOTOXIC CAPACITY AS WELL AS THE INCREASED EXPRESSION OF MULTIPLE CO-INHIBITORY RECEPTORS. PRECLINICAL TUMOR STUDIES AND CLINICAL COHORTS HAVE DEMONSTRATED THAT T CELL EXHAUSTION IS FIRMLY ASSOCIATED WITH POOR CLINICAL OUTCOMES IN A VARIETY OF CANCERS. MORE IMPORTANTLY, CD8(+) TEXS ARE REGARDED AS THE MAIN RESPONDER TO IMMUNE CHECKPOINT BLOCKADE (ICB). HOWEVER, TO DATE, A LARGE NUMBER OF CANCER PATIENTS HAVE FAILED TO ACHIEVE DURABLE RESPONSES AFTER ICB. THEREFORE, IMPROVING CD8(+) TEXS MAY BE A BREAKTHROUGH POINT TO REVERSE THE CURRENT DILEMMA OF CANCER IMMUNOTHERAPY AND ELIMINATE CANCERS. STRATEGIES TO REINVIGORATE CD8(+) TEXS IN TME MAINLY INCLUDE ICB, TRANSCRIPTION FACTOR-BASED THERAPY, EPIGENETIC THERAPY, METABOLISM-BASED THERAPY AND CYTOKINE THERAPY, WHICH TARGET ON DIFFERENT ASPECTS OF EXHAUSTION PROGRESSION. EACH OF THEM HAS ITS ADVANTAGES AND APPLICATION SCOPE. IN THIS REVIEW, WE MAINLY FOCUS ON THE MAJOR ADVANCES OF CURRENT STRATEGIES TO REINVIGORATE CD8(+) TEXS IN TME. WE SUMMARIZE THEIR EFFICACY AND MECHANISMS, IDENTIFY THE PROMISING MONOTHERAPY AND COMBINED THERAPY AND PROPOSE SUGGESTIONS TO ENHANCE THE TREATMENT EFFICACY TO SIGNIFICANTLY BOOST ANTI-TUMOR IMMUNITY AND ACHIEVE BETTER CLINICAL OUTCOMES. 2023 18 2409 28 EPIGENETIC SCARRING OF EXHAUSTED T CELLS HINDERS MEMORY DIFFERENTIATION UPON ELIMINATING CHRONIC ANTIGENIC STIMULATION. EXHAUSTED CD8 T CELLS (T(EX)) ARE A DISTINCT STATE OF T CELL DIFFERENTIATION ASSOCIATED WITH FAILURE TO CLEAR CHRONIC VIRUSES AND CANCER. IMMUNOTHERAPIES SUCH AS PD-1 BLOCKADE CAN REINVIGORATE T(EX) CELLS, BUT REINVIGORATION IS NOT DURABLE. A MAJOR UNANSWERED QUESTION IS WHETHER T(EX) CELLS DIFFERENTIATE INTO FUNCTIONAL DURABLE MEMORY T CELLS (T(MEM)) UPON ANTIGEN CLEARANCE. HERE, USING A MOUSE MODEL, WE FOUND THAT UPON ELIMINATING CHRONIC ANTIGENIC STIMULATION, T(EX) CELLS PARTIALLY (RE)ACQUIRE PHENOTYPIC AND TRANSCRIPTIONAL FEATURES OF T(MEM) CELLS. THESE 'RECOVERING' T(EX) CELLS ORIGINATED FROM THE T CELL FACTOR (TCF-1(+)) T(EX) PROGENITOR SUBSET. NEVERTHELESS, THE RECALL CAPACITY OF THESE RECOVERING T(EX) CELLS REMAINED COMPROMISED AS COMPARED TO T(MEM) CELLS. CHROMATIN-ACCESSIBILITY PROFILING REVEALED A FAILURE TO RECOVER CORE MEMORY EPIGENETIC CIRCUITS AND MAINTENANCE OF A LARGELY EXHAUSTED OPEN CHROMATIN LANDSCAPE. THUS, DESPITE SOME PHENOTYPIC AND TRANSCRIPTIONAL RECOVERY UPON ANTIGEN CLEARANCE, EXHAUSTION LEAVES DURABLE EPIGENETIC SCARS CONSTRAINING FUTURE IMMUNE RESPONSES. THESE RESULTS SUPPORT EPIGENETIC REMODELING INTERVENTIONS FOR T(EX) CELL-TARGETED IMMUNOTHERAPIES. 2021 19 5248 33 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 20 790 25 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