1   991 111 CHRONIC STIMULATION DRIVES HUMAN NK CELL DYSFUNCTION AND EPIGENETIC REPROGRAMING. A POPULATION OF NATURAL KILLER (NK) CELLS EXPRESSING THE ACTIVATING RECEPTOR NKG2C AND THE MATURATION MARKER CD57 EXPANDS IN RESPONSE TO HUMAN CYTOMEGALOVIRUS (HCMV) INFECTION. CD3-CD56DIMCD57+NKG2C+ NK CELLS ARE SIMILAR TO CD8+ MEMORY T CELLS WITH RAPID AND ROBUST EFFECTOR FUNCTION UPON RE-STIMULATION, PERSISTENCE, AND EPIGENETIC REMODELING OF THE IFNG LOCUS. CHRONIC ANTIGEN STIMULATION DRIVES CD8+ MEMORY T CELL PROLIFERATION WHILE ALSO INDUCING GENOME-WIDE EPIGENETIC REPROGRAMING AND DYSFUNCTION. WE HYPOTHESIZED THAT CHRONIC STIMULATION COULD SIMILARLY INDUCE EPIGENETIC REPROGRAMING AND DYSFUNCTION IN NK CELLS. HERE WE SHOW THAT CHRONIC STIMULATION OF ADAPTIVE NK CELLS THROUGH NKG2C USING PLATE-BOUND AGONISTIC ANTIBODIES IN COMBINATION WITH IL-15 DROVE ROBUST PROLIFERATION AND ACTIVATION OF CD3-CD56DIMCD57+NKG2C+ NK CELLS WHILE SIMULTANEOUSLY INDUCING HIGH EXPRESSION OF THE CHECKPOINT INHIBITORY RECEPTORS LAG-3 AND PD-1. MARKED INDUCTION OF CHECKPOINT INHIBITORY RECEPTORS WAS ALSO OBSERVED ON THE SURFACE OF ADAPTIVE NK CELLS CO-CULTURED WITH HCMV-INFECTED ENDOTHELIAL CELLS. CHRONICALLY STIMULATED ADAPTIVE NK CELLS WERE DYSFUNCTIONAL WHEN CHALLENGED WITH TUMOR TARGETS. THESE CELLS EXHIBITED A PATTERN OF EPIGENETIC REPROGRAMING, WITH GENOME-WIDE ALTERATIONS IN DNA METHYLATION. OUR STUDY HAS IMPORTANT IMPLICATIONS FOR CANCER IMMUNOTHERAPY AND SUGGEST THAT EXHAUSTED NK CELLS COULD BE TARGETED WITH INHIBITORY CHECKPOINT RECEPTOR BLOCKADE.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
2  4596  37 NATURAL KILLER CELLS IN HUMAN IMMUNODEFICIENCY VIRUS-1 INFECTION: SPOTLIGHT ON THE IMPACT OF HUMAN CYTOMEGALOVIRUS. HUMAN CYTOMEGALOVIRUS (HCMV) HAS BEEN CLOSELY ASSOCIATED WITH THE HUMAN RACE ACROSS EVOLUTIONARY TIME. HCMV CO-INFECTION IS NEARLY UNIVERSAL IN HUMAN IMMUNODEFICIENCY VIRUS-1 (HIV-1)-INFECTED INDIVIDUALS AND REMAINS AN IMPORTANT COFACTOR IN HIV-1 DISEASE PROGRESSION EVEN IN THE ERA OF EFFECTIVE ANTIRETROVIRAL TREATMENT. HCMV INFECTION HAS BEEN SHOWN TO HAVE A BROAD AND POTENT INFLUENCE ON THE HUMAN IMMUNE SYSTEM AND HAS BEEN LINKED WITH THE DISCOVERY AND CHARACTERIZATION OF ADAPTIVE NATURAL KILLER (NK) CELLS. DISTINCT NK-CELL SUBSETS, PREDOMINATELY EXPRESSING THE ACTIVATING RECEPTOR NKG2C AND THE MARKER OF TERMINAL DIFFERENTIATION CD57, EXPAND IN RESPONSE TO HCMV. THESE NK-CELL POPULATIONS ENGAGED IN THE LONG-LASTING INTERACTION WITH HCMV, IN ADDITION TO CHARACTERISTIC BUT VARIABLE EXPRESSION OF SURFACE RECEPTORS, EXHIBIT REDUCED EXPRESSION OF SIGNALING PROTEINS AND TRANSCRIPTION FACTORS EXPRESSED BY CANONICAL NK CELLS. BROAD EPIGENETIC MODIFICATIONS DRIVE THE EMERGENCE AND PERSISTENCE OF HCMV-ADAPTED NK CELLS THAT HAVE DISTINCT FUNCTIONAL CHARACTERISTICS. NKG2C(+) NK-CELL EXPANSIONS HAVE BEEN OBSERVED IN HIV-1 INFECTED PATIENTS AND OTHER ACUTE AND CHRONIC VIRAL INFECTIONS BEING SYSTEMATICALLY ASSOCIATED WITH HCMV SEROPOSITIVITY. THE LATTER IS POTENTIALLY AN IMPORTANT CONFOUNDING VARIABLE IN STUDIES FOCUSED ON THE CELLULAR NK-CELL RECEPTOR REPERTOIRE AND FUNCTIONAL CAPACITY. HERE, FOCUSING ON HIV-1 INFECTION WE REVIEW THE EVIDENCE IN FAVOR OF "ADAPTIVE" CHANGES LIKELY INDUCED BY HCMV CO-INFECTION IN NK-CELL SUBSETS. WE HIGHLIGHT A NUMBER OF KEY QUESTIONS AND HOW INSIGHTS INTO THE ADAPTIVE BEHAVIOR OF NK CELLS WILL INFORM NEW STRATEGIES EXPLOITING THEIR UNIQUE PROPERTIES IN THE FIGHT AGAINST HIV-1.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
3  4595  36 NATURAL KILLER CELLS AND IMMUNE-CHECKPOINT INHIBITOR THERAPY: CURRENT KNOWLEDGE AND NEW CHALLENGES. THE DISCOVERY OF IMMUNE CHECKPOINTS (ICS) AND THE DEVELOPMENT OF SPECIFIC BLOCKERS TO RELIEVE IMMUNE EFFECTOR CELLS FROM THIS INHIBITING MECHANISM HAS CHANGED THE VIEW OF ANTI-CANCER THERAPY. IN ADDITION TO CYTOTOXIC T LYMPHOCYTE ANTIGEN 4 (CTLA4) AND PROGRAMMED DEATH 1 (PD1), CLASSICAL ICS OF T LYMPHOCYTES AND RECENTLY DESCRIBED ALSO ON A FRACTION OF NATURAL KILLER (NK) CELLS, SEVERAL NK CELL RECEPTORS, INCLUDING KILLER IMMUNOGLOBULIN-LIKE INHIBITORY RECEPTORS (KIRS) AND NGK2A, HAVE BEEN RECOGNIZED AS CHECKPOINT MEMBERS TYPICAL OF THE NK CELL POPULATION. THIS OFFERS THE OPPORTUNITY OF A DUAL-CHECKPOINT INHIBITION APPROACH, TARGETING CLASSICAL AND NON-CLASSICAL ICS AND LEADING TO A SYNERGISTIC THERAPEUTIC EFFECT. IN THIS REVIEW, WE WILL OVERVIEW AND DISCUSS THIS NEW PERSPECTIVE, FOCUSING ON THE MOST RELEVANT CANDIDATES FOR THIS ROLE AMONG THE VARIETY OF POTENTIAL NK ICS. BESIDE LISTING AND DEFINING CLASSICAL ICS EXPRESSED ALSO BY NK CELLS, OR NON-CLASSICAL ICS EITHER ON T OR ON NK CELLS, WE WILL ADDRESS THEIR ROLE IN NK CELL SURVIVAL, CHRONIC STIMULATION OR FUNCTIONAL EXHAUSTION, AND THE POTENTIAL RELEVANCE OF THIS PHENOMENON ON ANTI-TUMOR IMMUNE RESPONSE. FURTHERMORE, NK ICS WILL BE PROPOSED AS POSSIBLE NEW TARGETS FOR THE DEVELOPMENT OF EFFICIENT COMBINED IMMUNOTHERAPY, NOT FORGETTING THE RELEVANT CONCERNS THAT MAY BE RAISED ON NK IC BLOCKADE. FINALLY, THE IMPACT OF EPIGENETIC DRUGS IN SUCH A COMPLEX THERAPEUTIC PICTURE WILL BE BRIEFLY ADDRESSED.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
4  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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
5  1735  36 EARLY AND SUSTAINED EXPANSION OF ADAPTIVE NATURAL KILLER CELLS FOLLOWING HAPLOIDENTICAL TRANSPLANTATION AND CTLA4IG-PRIMED DONOR LYMPHOCYTE INFUSIONS DISSOCIATE GRAFT-VERSUS-LEUKEMIA AND GRAFT-VERSUS-HOST EFFECTS. BACKGROUND: ADAPTIVE OR MEMORY NATURAL KILLER (NK) CELLS WITH EPIGENETIC IMPRINTS SIMILAR TO MEMORY T CELLS HAVE BEEN SHOWN TO DEVELOP IN RESPONSE TO CYTOMEGALOVIRUS (CMV) INFECTION WITH UPREGULATION OF ACTIVATING RECEPTOR NKG2C. THESE CELLS HAVE BEEN SHOWN TO POSSESS STRONG ANTI-TUMOUR EFFICACY BOTH IN-VITRO AS WELL AS IN-VIVO. OBJECTIVES: TO DETERMINE IF RECONSTITUTION OF ADAPTIVE NK CELLS (CD56(DIM)NKG2C(+)NKG2A(-)) IN PATIENTS WITH ADVANCED LEUKEMIA UNDERGOING HAPLOIDENTICAL HCT HAD ANY IMPACT ON DISEASE PROGRESSION (DP). STUDY DESIGN: THE STUDY COHORT COMPRISED OF 60 PATIENTS WITH ADVANCED ACUTE LEUKEMIA, AGED 2-65 YEARS, RECEIVING MYELOABLATIVE PTCY BASED HAPLOIDENTICAL TRANSPLANTATION FROM CMV SEROPOSITIVE DONORS, FOLLOWED BY CTLA4IG-PRIMED DONOR LYMPHOCYTE INFUSIONS (DLI). THEY WERE EVALUATED FOR THE KINETICS OF RECONSTITUTION OF ADAPTIVE NK CELLS, BOTH PHENOTYPIC AND FUNCTIONAL, AT DAYS +30,+60, +90 AND AT REGULAR INTERVALS, TO 3 YEARS OF FOLLOW-UP, IN RELATION TO DP. RECONSTITUTION OF ADAPTIVE NK CELLS WAS COMPARED WITH A RETROSPECTIVE COHORT OF PATIENTS IN THE SAME PROTOCOL RECEIVING DLI WITHOUT CTLA4IG. RESULTS: NON-RELAPSE MORTALITY, ACUTE AND CHRONIC GVHD WERE 5.1%, 10.3% AND 14.5%. DP WAS 17.5% AT A MEDIAN FOLLOW-UP OF 28 MONTHS. ADAPTIVE NK CELLS WERE SIGNIFICANTLY HIGHER IN PATIENTS WITHOUT DP AT DAYS+30, +60 AND +90 (P = 0.0001), IRRESPECTIVE OF CMV REACTIVATION AND REMAINED ELEVATED UNTIL 36 MONTHS POST-HCT. THESE CELLS MAINTAINED THEIR FUNCTIONAL COMPETENCE AS MEASURED BY ROBUST INTERFERON-GAMMA PRODUCTION WITH HIGHER EXPRESSIONS OF KIR, NKG2D AND CD57, WITHOUT ANY INCREASE IN PD1 EXPRESSION. GRAFTS FROM DONORS WITH HIGHER ADAPTIVE NK CELLS WERE ASSOCIATED WITH A LOWER RISK OF DP (P = 0.0001). IN MULTIVARIATE ANALYSIS, ADAPTIVE NK CELL RECOVERY AT DAY +90 HAD THE MOST FAVORABLE IMPACT ON DP (HR-0.7). TREGS RECONSTITUTED BRISKLY ALONG WITH THE ADAPTIVE NK CELLS AND WERE SUSTAINED AS WELL, WITHOUT COMPROMISING THE GVL EFFECT. COMPARISON WITH A RETROSPECTIVE COHORT RECEIVING THE SAME PROTOCOL WITH DLI WITHOUT CTLA4IG, SHOWED A SUPERIOR RECONSTITUTION OF ADAPTIVE NK CELLS IN THOSE RECEIVING CTLA4IG-DLI (P < 0.0001). CONCLUSION: OUR STUDY SUGGESTS THAT MYELOABLATIVE TRANSPLANTATION FROM CMV SEROPOSITIVE HAPLOIDENTICAL DONORS AUGMENTED WITH CTLA4IG-PRIMED DLI MIGHT FAVOR EARLY AND SUSTAINED EXPANSION OF FUNCTIONALLY COMPETENT ADAPTIVE NK CELLS IRRESPECTIVE OF CMV REACTIVATION, WITH A FAVORABLE OUTCOME.	2021	

6  5849  35 SUBEROYLANILIDE HYDROXAMIC ACID (SAHA) AND CLADRIBINE SYNERGISTICALLY INDUCE APOPTOSIS IN NK-LGL LEUKAEMIA. NATURAL KILLER (NK) LARGE GRANULAR LYMPHOCYTE (LGL) LEUKAEMIA FEATURES A CLONAL PROLIFERATION OF CD3(-) NK CELLS THAT CAN BE CLASSIFIED INTO EITHER AGGRESSIVE OR CHRONIC CATEGORIES. THE NKL CELL LINE, DERIVED FROM AN AGGRESSIVE ASIAN NK CELL LEUKAEMIA, AND PATIENT SAMPLES FROM CHRONIC NK-LGL LEUKAEMIA WERE USED IN OUR STUDY TO PROBE FOR SYNERGISTIC EFFICACY OF THE EPIGENETIC DRUGS VORINOSTAT (SAHA) AND CLADRIBINE IN THIS DISEASE. WE DEMONSTRATE THAT HISTONE DEACETYLASES (HDACS) ARE OVER-EXPRESSED IN BOTH AGGRESSIVE AND CHRONIC NK LEUKAEMIA. ADMINISTRATION OF THE HDAC INHIBITOR SAHA REDUCES CLASS I AND II HDAC EXPRESSION AND ENHANCES HISTONE ACETYLATION IN LEUKAEMIC NK CELLS. IN VITRO COMBINATION TREATMENT WITH SAHA AND CLADRIBINE DOSE-DEPENDENTLY EXERTS SYNERGISTIC CYTOTOXIC AND APOPTOTIC EFFECTS ON LEUKAEMIC NK CELLS. EXPRESSION PROFILING OF APOPTOTIC REGULATORY GENES SUGGESTS THAT BOTH COMPOUNDS LED TO CASPASE-DEPENDENT APOPTOSIS THROUGH ACTIVATION OF INTRINSIC MITOCHONDRIAL AND EXTRINSIC DEATH RECEPTOR PATHWAYS. COLLECTIVELY, THESE DATA SHOW THAT COMBINED EPIGENETIC THERAPY, USING HDAC AND DNA METHYLTRANSFERASE INHIBITORS, MAY BE A PROMISING THERAPEUTIC APPROACH FOR NK-LGL LEUKAEMIA.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
7  2421  35 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
8  1657  30 DOWN-EXPRESSION OF MIR-152 LEAD TO IMPAIRED ANTI-TUMOR EFFECT OF NK VIA UPREGULATION OF HLA-G. IT IS KNOWN THAT CHRONIC HBV INFECTION (CHB) IS THE MAJOR RISK FACTOR FOR HEPATOCELLULAR CARCINOMA (HCC) BECAUSE CHB COULD NOT ONLY CAUSE LIVER TUMORIGENESIS BUT ALSO LEAD TO CHANGE OF LOCAL MICROENVIROMENT AND LOWER IMMUNE RESPONSE TO INFECTED AND CANCEROUS CELLS (IMMUNE TOLERANCE). HUMAN LEUCOCYTE ANTIGEN-G (HLA-G) BELONGS TO A NON-CLASSIC MHC-I FAMILY AND WAS CONSIDERED TO BE AN IMMUNE TOLERANCE MOLECULE, WHICH COULD BIND TO IMMUNOSUPPRESSIVE RECEPTORS OF NATURAL KILLER CELL (NK) AND T CELLS AND TRIGGER IMMUNOSUPPRESSIVE SIGNALING. RECENTLY, NUMEROUS STUDIES HIGHLIGHTED THAT MICRORNAS (MIRNAS) WERE SIGNIFICANTLY DIFFERENTIALLY EXPRESSED IN HCC TUMORIGENESIS, AND THE EXPRESSION WAS TISSUE-SPECIFIC, INDICATING THAT MIRNAS MAY CAUSE GREAT EPIGENETIC CHANGES IN HCC TUMORIGENESIS. IN THIS STUDY, WE FOUND THAT THE EXPRESSION OF HLA-G WAS UPREGULATED BY HEPATITIS B VIRUS (HBV) INFECTION AND MIR-152; A HLA-G-TARGETING MIRNA WAS DOWNREGULATED BY HBV INFECTION. AND HIGH EXPRESSION OF HLA-G FURTHER SUPPRESSED NK AGAINST CANCER CELLS, PROVIDING A NEW CONCEPT THAT MIR-152 WAS INVOLVED IN HBV-INDUCED HEPATOCELLULAR CARCINOMA.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
9  5593  37 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
10  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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
11  6481  39 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
12   771  36 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
13  1349  23 DETERMINANTS OF INNATE IMMUNITY IN VISCERAL LEISHMANIASIS AND THEIR IMPLICATION IN VACCINE DEVELOPMENT. LEISHMANIASIS IS ENDEMIC TO THE TROPICAL AND SUBTROPICAL REGIONS OF THE WORLD AND IS TRANSMITTED BY THE BITE OF AN INFECTED SAND FLY. THE MULTIFACETED INTERACTIONS BETWEEN LEISHMANIA, THE HOST INNATE IMMUNE CELLS, AND THE ADAPTIVE IMMUNITY DETERMINE THE SEVERITY OF PATHOGENESIS AND DISEASE DEVELOPMENT. LEISHMANIA PARASITES ESTABLISH A CHRONIC INFECTION BY SUBVERSION AND ATTENUATION OF THE MICROBICIDAL FUNCTIONS OF PHAGOCYTIC INNATE IMMUNE CELLS SUCH AS NEUTROPHILS, MACROPHAGES AND DENDRITIC CELLS (DCS). OTHER INNATE CELLS SUCH AS INFLAMMATORY MONOCYTES, MAST CELLS AND NK CELLS, ALSO CONTRIBUTE TO RESISTANCE AND/OR SUSCEPTIBILITY TO LEISHMANIA INFECTION. IN ADDITION TO THE CYTOKINE/CHEMOKINE SIGNALS FROM THE INNATE IMMUNE CELLS, RECENT STUDIES IDENTIFIED THE SUBTLE SHIFTS IN THE METABOLIC PATHWAYS OF THE INNATE CELLS THAT ACTIVATE DISTINCT IMMUNE SIGNAL CASCADES. THE NEXUS BETWEEN METABOLIC PATHWAYS, EPIGENETIC REPROGRAMMING AND THE IMMUNE SIGNALING CASCADES THAT DRIVE THE DIVERGENT INNATE IMMUNE RESPONSES, REMAINS TO BE FULLY UNDERSTOOD IN LEISHMANIA PATHOGENESIS. FURTHER, DEVELOPMENT OF SAFE AND EFFICACIOUS VACCINES AGAINST LEISHMANIASIS REQUIRES A BROADER UNDERSTANDING OF THE EARLY INTERACTIONS BETWEEN THE PARASITES AND INNATE IMMUNE CELLS. IN THIS REVIEW WE FOCUS ON THE CURRENT UNDERSTANDING OF THE SPECIFIC ROLE OF INNATE IMMUNE CELLS, THE METABOLOMIC AND EPIGENETIC REPROGRAMMING AND IMMUNE REGULATION THAT OCCURS DURING VISCERAL LEISHMANIASIS, AND THE STRATEGIES USED BY THE PARASITE TO EVADE AND MODULATE HOST IMMUNITY. WE HIGHLIGHT HOW SUCH PATHWAYS COULD BE EXPLOITED IN THE DEVELOPMENT OF SAFE AND EFFICACIOUS LEISHMANIA VACCINES.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
14  5223  33 PRIMARY MURINE CD4+ T CELLS FAIL TO ACQUIRE THE ABILITY TO PRODUCE EFFECTOR CYTOKINES WHEN ACTIVE RAS IS PRESENT DURING TH1/TH2 DIFFERENTIATION. CONSTITUTIVE RAS SIGNALING HAS BEEN SHOWN TO AUGMENT IL-2 PRODUCTION, REVERSE ANERGY, AND FUNCTIONALLY REPLACE MANY ASPECTS OF CD28 CO-STIMULATION IN CD4+ T CELLS. THESE DATA RAISE THE POSSIBILITY THAT INTRODUCTION OF ACTIVE RAS INTO PRIMARY T CELLS MIGHT RESULT IN IMPROVED FUNCTIONALITY IN PATHOLOGIC SITUATIONS OF T CELL DYSFUNCTION, SUCH AS CANCER OR CHRONIC VIRAL INFECTION. TO TEST THE BIOLOGIC EFFECTS OF ACTIVE RAS IN PRIMARY T CELLS, CD4+ T CELLS FROM COXSACKIE-ADENOVIRUS RECEPTOR TRANSGENIC MICE WERE TRANSDUCED WITH AN ADENOVIRUS ENCODING ACTIVE RAS. AS EXPECTED, ACTIVE RAS AUGMENTED IL-2 PRODUCTION IN NAIVE CD4+ T CELLS. HOWEVER, WHEN CELLS WERE CULTURED FOR 4 DAYS UNDER CONDITIONS TO PROMOTE EFFECTOR CELL DIFFERENTIATION, ACTIVE RAS INHIBITED THE ABILITY OF CD4+ T CELLS TO ACQUIRE A TH1 OR TH2 EFFECTOR CYTOKINE PROFILE. THIS DIFFERENTIATION DEFECT WAS NOT DUE TO DEFICIENT STAT4 OR STAT6 ACTIVATION BY IL-12 OR IL-4, RESPECTIVELY, NOR WAS IT ASSOCIATED WITH DEFICIENT INDUCTION OF T-BET AND GATA-3 EXPRESSION. IMPAIRED EFFECTOR CYTOKINE PRODUCTION IN ACTIVE RAS-TRANSDUCED CELLS WAS ASSOCIATED WITH DEFICIENT DEMETHYLATION OF THE IL-4 GENE LOCUS. OUR RESULTS INDICATE THAT, DESPITE AUGMENTING ACUTE ACTIVATION OF NAIVE T CELLS, CONSTITUTIVE RAS SIGNALING INHIBITS THE ABILITY OF CD4+ T CELLS TO PROPERLY DIFFERENTIATE INTO TH1/TH2 EFFECTOR CYTOKINE-PRODUCING CELLS, IN PART BY INTERFERING WITH EPIGENETIC MODIFICATION OF EFFECTOR GENE LOCI. ALTERNATIVE STRATEGIES TO POTENTIATE RAS PATHWAY SIGNALING IN T CELLS IN A MORE REGULATED FASHION SHOULD BE CONSIDERED AS A THERAPEUTIC APPROACH TO IMPROVE IMMUNE RESPONSES IN VIVO.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
15  1040  24 CLINICAL AND GENETIC CHARACTERIZATION OF EPSTEIN-BARR VIRUS-ASSOCIATED T/NK-CELL LYMPHOPROLIFERATIVE DISEASES. BACKGROUND: EPSTEIN-BARR VIRUS (EBV)-ASSOCIATED T-/NATURAL KILLER (T/NK)-CELL LYMPHOPROLIFERATIVE DISEASES CLINICALLY TAKE ON VARIOUS FORMS, RANGING FROM AN INDOLENT COURSE TO AN AGGRESSIVE CONDITION. OBJECTIVE: CLINICALLY, FAILURE TO ESTABLISH PRECISE DIAGNOSIS AND PROVIDE PROPER TREATMENT MAKES IT DIFFICULT TO HELP PATIENTS. WE SOUGHT TO BETTER UNDERSTAND THE UNDERLYING PATHOGENESIS AND TO IDENTIFY GENETIC PROGNOSTIC FACTORS TO ACHIEVE BETTER TREATMENT EFFICACY. METHODS: IN THIS STUDY, 119 CASES OF EBV-ASSOCIATED LYMPHOPROLIFERATIVE DISEASES, INCLUDING EBV-ASSOCIATED HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS (N = 46) AND CHRONIC ACTIVE EBV DISEASE OF T/NK CELL TYPE (N = 73), WERE RETROSPECTIVELY EXAMINED. RESULTS: ADULTS AGED >20 YEARS AT ONSET ACCOUNTED FOR 71.4% OF OUR COHORT. ABOUT 54.6% PATIENTS WITH UNFAVORABLE OVERALL SURVIVAL DEVELOPED HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS AND HAD HIGHER PLASMA EBV LOAD. ALLOGENIC HEMATOPOIETIC STEM-CELL TRANSPLANTATION WAS THE SOLE INDEPENDENT FAVORABLE FACTOR. WE SYSTEMATICALLY SCREENED GERMLINE AND SOMATIC ABERRATIONS BY WHOLE-EXOME AND TARGETED SEQUENCING. AMONG 372 ANTIVIRAL IMMUNITY GENES, GERMLINE VARIANTS OF 8 GENES WERE SIGNIFICANTLY ENRICHED. FROM A PANEL OF 24 DRIVER GENES, SOMATIC MUTATIONS WERE FREQUENTLY IDENTIFIED IN DOMINANT EBV-INFECTED T/NK CELLS. PATIENTS CARRYING ANY GERMLINE/SOMATIC ABERRATIONS IN EPIGENETIC MODIFIERS AND RIG-I-LIKE RECEPTOR (RLR) PATHWAY HAD WORSE OVERALL SURVIVAL THAN THOSE WITHOUT 2 TYPE ABERRATIONS. IMPORTANTLY, PATIENTS WITH IFIH1 AND/OR DDX3X ABERRATIONS IN THE RLR PATHWAY HAD HIGHER PLASMA AND NK-CELL EBV LOAD. KNOCKDOWN OF DDX3X IN NKYS CELLS DOWNREGULATED RLR SIGNALING ACTIVITIES AND ELEVATED THE EXPRESSION OF EBV-ENCODED ONCOGENES SUCH AS LMP1 AND EBNA1. CONCLUSION: GENETIC DEFECTS WERE PREVALENT IN ADULT EBV-ASSOCIATED HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS PATIENTS AND PATIENTS WITH CHRONIC ACTIVE EBV DISEASE OF T/NK CELL TYPE; THESE DEFECTS WERE ASSOCIATED WITH UNFAVORABLE PROGNOSIS. THESE FINDINGS CAN HELP CLINICIANS WORK OUT MORE PRECISE STAGING OF THE CONDITION AND PROVIDE NEW INSIGHTS INTO THESE EBV-ASSOCIATED DISEASES.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                      
16  2392  35 EPIGENETIC REPRESSION OF INTERLEUKIN 2 EXPRESSION IN SENESCENT CD4+ T CELLS DURING CHRONIC HIV TYPE 1 INFECTION. THE MOLECULAR MECHANISMS FOR IL2 GENE-SPECIFIC DYSREGULATION DURING CHRONIC HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 (HIV-1) INFECTION ARE UNKNOWN. HERE, WE INVESTIGATED THE ROLE OF DNA METHYLATION IN SUPPRESSING INTERLEUKIN 2 (IL-2) EXPRESSION IN MEMORY CD4(+) T CELLS DURING CHRONIC HIV-1 INFECTION. WE OBSERVED THAT CPG SITES IN THE IL2 PROMOTER OF CD4(+) T CELLS WERE FULLY METHYLATED IN NAIVE CD4(+) T CELLS AND SIGNIFICANTLY DEMETHYLATED IN THE MEMORY POPULATIONS. INTERESTINGLY, WE FOUND THAT THE MEMORY CELLS THAT HAD A TERMINALLY DIFFERENTIATED PHENOTYPE AND EXPRESSED CD57 HAD INCREASED IL2 PROMOTER METHYLATION RELATIVE TO LESS DIFFERENTIATED MEMORY CELLS IN HEALTHY INDIVIDUALS. IMPORTANTLY, EARLY EFFECTOR MEMORY SUBSETS FROM HIV-1-INFECTED SUBJECTS EXPRESSED HIGH LEVELS OF CD57 AND WERE HIGHLY METHYLATED AT THE IL2 LOCUS. FURTHERMORE, THE INCREASED CD57 EXPRESSION ON MEMORY CD4(+) T CELLS WAS INVERSELY CORRELATED WITH IL-2 PRODUCTION. THESE DATA SUGGEST THAT DNA METHYLATION AT THE IL2 LOCUS IN CD4(+) T CELLS IS COUPLED TO IMMUNOSENESCENCE AND PLAYS A CRITICAL ROLE IN THE BROAD DYSFUNCTION THAT OCCURS IN POLYCLONAL T CELLS DURING HIV-1 INFECTION.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
17  4726  23 NOT-SO-OPPOSITE ENDS OF THE SPECTRUM: CD8(+) T CELL DYSFUNCTION ACROSS CHRONIC INFECTION, CANCER AND AUTOIMMUNITY. CD8(+) T CELLS ARE CRITICAL MEDIATORS OF CYTOTOXIC EFFECTOR FUNCTION IN INFECTION, CANCER AND AUTOIMMUNITY. IN CANCER AND CHRONIC VIRAL INFECTION, CD8(+) T CELLS UNDERGO A PROGRESSIVE LOSS OF CYTOKINE PRODUCTION AND CYTOTOXICITY, A STATE TERMED T CELL EXHAUSTION. IN AUTOIMMUNITY, AUTOREACTIVE CD8(+) T CELLS RETAIN THE CAPACITY TO EFFECTIVELY MEDIATE THE DESTRUCTION OF HOST TISSUES. ALTHOUGH THE CLINICAL OUTCOME DIFFERS IN EACH CONTEXT, CD8(+) T CELLS ARE CHRONICALLY EXPOSED TO ANTIGEN IN ALL THREE. THESE CHRONICALLY STIMULATED CD8(+) T CELLS SHARE SOME COMMON PHENOTYPIC FEATURES, AS WELL AS TRANSCRIPTIONAL AND EPIGENETIC PROGRAMMING, ACROSS DISEASE CONTEXTS. A BETTER UNDERSTANDING OF THESE CD8(+) T CELL STATES MAY REVEAL NOVEL STRATEGIES TO AUGMENT CLEARANCE OF CHRONIC VIRAL INFECTION AND CANCER AND TO MITIGATE SELF-REACTIVITY LEADING TO TISSUE DAMAGE IN AUTOIMMUNITY.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
18  5896  32 T CELLS IN HEALTH AND DISEASE. T CELLS ARE CRUCIAL FOR IMMUNE FUNCTIONS TO MAINTAIN HEALTH AND PREVENT DISEASE. T CELL DEVELOPMENT OCCURS IN A STEPWISE PROCESS IN THE THYMUS AND MAINLY GENERATES CD4(+) AND CD8(+) T CELL SUBSETS. UPON ANTIGEN STIMULATION, NAIVE T CELLS DIFFERENTIATE INTO CD4(+) HELPER AND CD8(+) CYTOTOXIC EFFECTOR AND MEMORY CELLS, MEDIATING DIRECT KILLING, DIVERSE IMMUNE REGULATORY FUNCTION, AND LONG-TERM PROTECTION. IN RESPONSE TO ACUTE AND CHRONIC INFECTIONS AND TUMORS, T CELLS ADOPT DISTINCT DIFFERENTIATION TRAJECTORIES AND DEVELOP INTO A RANGE OF HETEROGENEOUS POPULATIONS WITH VARIOUS PHENOTYPE, DIFFERENTIATION POTENTIAL, AND FUNCTIONALITY UNDER PRECISE AND ELABORATE REGULATIONS OF TRANSCRIPTIONAL AND EPIGENETIC PROGRAMS. ABNORMAL T-CELL IMMUNITY CAN INITIATE AND PROMOTE THE PATHOGENESIS OF AUTOIMMUNE DISEASES. IN THIS REVIEW, WE SUMMARIZE THE CURRENT UNDERSTANDING OF T CELL DEVELOPMENT, CD4(+) AND CD8(+) T CELL CLASSIFICATION, AND DIFFERENTIATION IN PHYSIOLOGICAL SETTINGS. WE FURTHER ELABORATE THE HETEROGENEITY, DIFFERENTIATION, FUNCTIONALITY, AND REGULATION NETWORK OF CD4(+) AND CD8(+) T CELLS IN INFECTIOUS DISEASE, CHRONIC INFECTION AND TUMOR, AND AUTOIMMUNE DISEASE, HIGHLIGHTING THE EXHAUSTED CD8(+) T CELL DIFFERENTIATION TRAJECTORY, CD4(+) T CELL HELPER FUNCTION, T CELL CONTRIBUTIONS TO IMMUNOTHERAPY AND AUTOIMMUNE PATHOGENESIS. WE ALSO DISCUSS THE DEVELOPMENT AND FUNCTION OF GAMMADELTA T CELLS IN TISSUE SURVEILLANCE, INFECTION, AND TUMOR IMMUNITY. FINALLY, WE SUMMARIZED CURRENT T-CELL-BASED IMMUNOTHERAPIES IN BOTH CANCER AND AUTOIMMUNE DISEASES, WITH AN EMPHASIS ON THEIR CLINICAL APPLICATIONS. A BETTER UNDERSTANDING OF T CELL IMMUNITY PROVIDES INSIGHT INTO DEVELOPING NOVEL PROPHYLACTIC AND THERAPEUTIC STRATEGIES IN HUMAN DISEASES.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
19  3538  23 IMMUNE REGULATION IN CHRONIC HEPATITIS C VIRUS INFECTION. THE IMMUNOLOGICAL RESULT OF INFECTION WITH HEPATITIS C VIRUS (HCV) DEPENDS ON THE DELICATE BALANCE BETWEEN A VIGOROUS IMMUNE RESPONSE THAT MAY CLEAR THE INFECTION, BUT WITH A RISK OF UNSPECIFIC INFLAMMATION AND, OR A LESS INFLAMMATORY RESPONSE THAT LEADS TO CHRONIC INFECTION. IN GENERAL, EXHAUSTION AND IMPAIRMENT OF CYTOTOXIC FUNCTION OF HCV-SPECIFIC T CELLS AND NK CELLS ARE FOUND IN PATIENTS WITH CHRONIC HCV INFECTION. IN CONTRAST, AN INCREASE IN IMMUNE REGULATORY FUNCTIONS IS FOUND PRIMARILY IN FORM OF INCREASED IL-10 PRODUCTION POSSIBLY DUE TO INCREASED LEVEL AND FUNCTION OF ANTI-INFLAMMATORY TREGS. THUS, THE MAJOR IMMUNE PLAYERS DURING CHRONIC HCV INFECTION ARE CHARACTERIZED BY A DECREASE OF CYTOTOXIC FUNCTION AND INCREASE OF INHIBITORY FUNCTIONS. THIS MAY BE AN APPROACH TO DIMINISH INTRAHEPATIC AND SYSTEMIC INFLAMMATION. FINALLY, THERE HAS BEEN INCREASING AWARENESS OF REGULATORY FUNCTIONS OF EPIGENETIC CHANGES IN CHRONIC HCV INFECTION. A VAST AMOUNT OF STUDIES HAVE REVEALED THE COMPLEXITY OF IMMUNE REGULATION IN CHRONIC HCV INFECTION, BUT THE INTERPLAY BETWEEN IMMUNE REGULATION IN VIRUS AND HOST REMAINS INCOMPLETELY UNDERSTOOD. THIS REVIEW PROVIDES AN OVERVIEW OF REGULATORY FUNCTIONS OF HCV-SPECIFIC T CELLS, NK CELLS, TREGS, IL-10, AND TGF-BETA, AS WELL AS EPIGENETIC CHANGES IN THE SETTING OF CHRONIC HCV INFECTION.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
20  2660  37 EPITHERAPY AND IMMUNE CHECKPOINT BLOCKADE: USING EPIGENETIC REINVIGORATION OF EXHAUSTED AND DYSFUNCTIONAL T CELLS TO REIMBURSE IMMUNOTHERAPY RESPONSE. BACKGROUND: CANCER CELLS SUBVERT NATURAL IMMUNOSUPPRESSION BY UPREGULATING THE EXPRESSION OF CHECKPOINT PROTEINS AND THEIR LIGANDS. FOR EXAMPLE, TUMOR CELLS EXPRESSING PROGRAMMED DEATH-LIGAND 1 (PD-L1) INDUCE IMMUNE CELL TOLERANCE TO CANCERS, THEREBY FACILITATING TUMOR PROGRESSION. THE RECENT CLINICAL SUCCESS OF IMMUNOTHERAPY, PARTICULARLY CHECKPOINT BLOCKADE, REPRESENTS A SIGNIFICANT ADVANCE IN CANCER THERAPY. HOWEVER, MANY CANCERS DEVELOP RESISTANCE TO IMMUNOTHERAPIES, AND THE UNDERLYING MECHANISMS AND HOW THESE MIGHT BE EXPLOITED TO OVERCOME RESISTANCE STILL NEED TO BE DETERMINED. METHODS: T CELL DYSFUNCTION, IN PART CAUSED BY CHRONIC T CELL RECEPTOR STIMULATION, DIMINISHES THE CAPACITY FOR DURABLE RESPONSES TO CHECKPOINT BLOCKADE. FURTHERMORE, T CELL POPULATIONS ARE PHENOTYPICALLY AND FUNCTIONALLY HETEROGENEOUS, RESULTING IN VARYING RESPONSES TO CHECKPOINT BLOCKADE. RECENT MOLECULAR STUDIES OF T CELL HETEROGENEITY HAVE SHOWN THAT CHECKPOINT BLOCKADE ON ITS OWN DOES NOT ALTER THE EPIGENETIC LANDSCAPE OF T CELLS, DESPITE EPIGENETIC CHANGES GOVERNING T CELL PHENOTYPE. CONCLUSION: HERE WE ARGUE THAT EPIGENETIC MODIFIERS CAN BE USED TO PRIME AND SENSITIZE T CELLS TO IMMUNOTHERAPY. ADMINISTERING EPITHERAPY IN CONJUNCTION WITH CHECKPOINT BLOCKADE COULD DECREASE T CELL EXHAUSTION AND IMMUNOTHERAPY RESISTANCE IN MANY CANCER TYPES.	2020