1 740 236 CANCER/TESTIS ANTIGENS: EXPRESSION, REGULATION, TUMOR INVASION, AND USE IN IMMUNOTHERAPY OF CANCERS. CANCER/TESTIS ANTIGENS (CTAS) ARE NAMED BASED ON THEIR EXPRESSION PATTERN THAT IS RESTRICTED IN A NUMBER OF NORMAL AND ABNORMAL TISSUES. TUMOR CELLS FREQUENTLY EXPRESS ANTIGENS WHOSE EXPRESSION IS TYPICALLY RESTRICTED TO GERM CELLS. THEIR UNIQUE EXPRESSION PATTERN IS GUARANTEED BY PRECISE EPIGENETIC REGULATORY MECHANISMS. BECAUSE OF THEIR TUMOR-LIMITED, HIGH IMMUNOGENICITY, AND BIASED EXPRESSION, DISCOVERY OF THESE MOLECULES PROVIDES UNPRECEDENTED OPPORTUNITIES FOR FURTHER RESEARCH AND CLINICAL DEVELOPMENT IN THE FIELD OF CANCER DIAGNOSIS AND IMMUNOTHERAPY. EVOLVING EVIDENCE REVEALS THAT A NUMBER OF CTAS STIMULATE EPITHELIAL MESENCHYMAL TRANSITION (EMT) AND GENERATION OF CANCER STEM-LIKE CELLS, INTENSIFYING METASTASIS, INVASION, AND TUMORIGENESIS. BASED ON THESE FEATURES, CTAS ATTRACT ATTENTION TO BE CONSIDERED AS IDEAL TARGETS FOR DEVELOPING SEVERAL CLINICAL TRIALS, MANY OF THEM CONCENTRATING ON CTA VACCINE THERAPY. ACCORDING TO RECENT PRACTICAL CLINICAL INTEREST, MORE CHARACTERIZATIONS OF CTA REGULATION ARE IDENTIFIED. CTA EXPRESSION HAS BEEN DEMONSTRATED IN A VARIETY OF HUMAN CANCER TISSUES, AND SOME OF THEM HAVE BEEN FOUND TO ELICIT HUMORAL AND/OR CELLULAR IMMUNE RESPONSES IN CANCER PATIENTS. CTAS ARE BRILLIANT TARGETS FOR ANTICANCER DRUG DISCOVERY, TARGETED TUMOR THERAPY, AND DIAGNOSTIC BIOMARKERS, FURTHERMORE, VALUED GENES IN THE STUDY OF IMMUNOTHERAPY, PROMOTING TUMORIGENESIS, AND MALIGNANT PROGRESSION. THIS REVIEW OUTLINES AND CATEGORIZES OUR CURRENT UNDERSTANDING OF THE COMPLEX AND BIASED PROCESS OF CTAS MRNA AND PROTEIN EXPRESSION IN CANCER, AND SUPPLIES THE MOST RECENT INFORMATION ON THEIR REGULATION AND FUNCTION. BESIDES, A CONCISE SYNOPSIS OF THE MAJOR CLINICAL TRIALS INVOLVING CTAS, AS THERAPEUTIC AVENUES, IS DISCUSSED. ABBREVIATIONS: AIRE: AUTOIMMUNE REGULATOR; CAMP: CYCLIC ADENOSINE 3',5'-CYCLIC MONOPHOSPHATE; CEA: CARCINOEMBRYONIC ANTIGEN; CML: CHRONIC MYELOID LEUKEMIA; CREB: CYCLICAMP RESPONSE ELEMENT BINDING; CSCS: CANCER STEM CELLS; CTAS: CANCER/TESTIS ANTIGENS; CTL: CYTOTOXIC T LYMPHOCYTE; DCS: DENDRITIC CELLS; EMT: EPITHELIAL-MESENCHYMAL TRANSITION; ERK: EXTRACELLULAR SIGNAL-REGULATED KINASE; ESCC: ESOPHAGEAL SQUAMOUS CELL CARCINOMA; ETS: E26 TRANSFORMATION-SPECIFIC; HIS: HISTIDINE; HLA: HUMAN LEUKOCYTE ANTIGEN; HNSCC: HEAD AND NECK SQUAMOUS CELL CARCINOMA; IFN-GAMMA: INTERFERON-GAMMA; IHC: IMMUNOHISTOCHEMISTRY; IL-7: INTERLEUKIN7; MHC: MAJOR HISTOCOMPATIBILITY COMPLEX; MMP2: MATRIX METALLOPROTEINASE 2; MTECS: MEDULLARY THYMUS EPITHELIAL CELLS; MUC1: MUCIN 1; NSCLC: NON-SMALL CELL LUNG CANCER; PRAME: PREFERENTIALLY EXPRESSED ANTIGEN IN MELANOMA; RDA: REPRESENTATIONAL DIFFERENCE ANALYSIS; SEREX: SEROLOGICAL ANALYSIS OF CDNA EXPRESSION; SSX: SYNOVIAL SARCOMA X CHROMOSOME; TAAS: TUMOR-ASSOCIATED ANTIGENS; TCR: T-CELL RECEPTOR; TCGA: THE CANCER GENOME ATLAS; TGF-BETA: TRANSFORMING GROWTH FACTOR-BETA. 2016 2 3099 28 GENOMIC DNA METHYLATION SIGNATURES IN DIFFERENT TISSUES AFTER AMBIENT AIR PARTICULATE MATTER EXPOSURE. DNA METHYLATION (5-MC) IS ONE OF THE SEVERAL EPIGENETIC MARKERS, AND IS GENERALLY ASSOCIATED WITH THE INHIBITION OF GENE EXPRESSION. BOTH HYPER AND HYPO DNA METHYLATION ARE ASSOCIATED WITH THE DISEASES. EXPOSURE TO FINE PARTICLES WITH A DIAMETER OF 2.5 MUM OR LESS (PM(2.5)) IS A PERVASIVE RISK FACTOR FOR CARDIOPULMONARY MORTALITY, METABOLIC DISORDERS, COGNITION DAMAGE, AND ETC.. RECENT REPORTS POINTED TOWARD THAT THESE DISEASES WERE ASSOCIATED WITH THE ALTERED DNA METHYLATION LEVEL OF SOME SPECIFIC-GENE, POTENTIALLY SUGGESTING THAT THE DNA METHYLATION ALTERATION WAS INVOLVED IN THE HEALTH HAZARD DERIVED FROM THE PM(2.5) EXPOSURE. IN THIS STUDY, WE SYSTEMATICALLY INVESTIGATED THE GLOBAL DNA METHYLATION LEVEL OF MOST TISSUES, INCLUDING LUNG, HEART, TESTIS, THYMUS, SPLEEN, EPIDIDYMAL FAT, HIPPOCAMPUS, KIDNEY, LIVE, AFTER SHORT AND LONG TERM PM(2.5) EXPOSURE. AFTER ACUTE PM(2.5) EXPOSURE, THE GLOBAL HYPO-METHYLATION IN DNA WAS OBSERVED IN LUNG AND HEART. NOTABLY, AFTER CHRONIC PM(2.5) EXPOSURE, LEVEL OF GLOBAL DNA METHYLATION DECREASED IN MOST ORGANS WHICH INCLUDED LUNG, TESTIS, THYMUS, SPLEEN, EPIDIDYMAL FAT, HIPPOCAMPUS AND BLOOD. THE PRESENT STUDY SYSTEMATICALLY DEMONSTRATED THE GLOBAL DNA METHYLATION CHANGES BY PM(2.5) EXPOSURE, AND PUT FORWARD A POSSIBLE ORIENTATION FOR FURTHER EXPLORING THE EFFECTS OF AMBIENT AIR PARTICLES EXPOSURE ON THE SPECIFIC ORGANS. 2019 3 5156 32 PRE-BIRTH ORIGINS OF ALLERGY AND ASTHMA. ALLERGY IS A CHRONIC DISEASE THAT CAN DEVELOP AS EARLY AS INFANCY, SUGGESTING THAT EARLY LIFE FACTORS ARE IMPORTANT IN ITS AETIOLOGY. VARIABLE ASSOCIATIONS BETWEEN SIZE AT BIRTH, A CRUDE MARKER OF THE FETAL ENVIRONMENT, AND ALLERGY HAVE BEEN REPORTED IN HUMANS AND REQUIRE COMPREHENSIVE REVIEW. ASSOCIATIONS BETWEEN BIRTH WEIGHT AND ALLERGY ARE HOWEVER CONFOUNDED IN HUMANS, AND WE AND OTHERS HAVE THEREFORE BEGUN EXPLORING THE EFFECTS OF EARLY LIFE EVENTS ON ALLERGY IN EXPERIMENTAL MODELS. IN PARTICULAR, WE ARE USING OVINE MODELS TO INVESTIGATE WHETHER AND HOW A RESTRICTED ENVIRONMENT BEFORE BIRTH PROTECTS AGAINST ALLERGY, WHETHER METHYL DONOR AVAILABILITY CONTRIBUTES TO ALLERGIC PROTECTION IN IUGR, AND WHY MATERNAL ASTHMA DURING PREGNANCY IS ASSOCIATED WITH INCREASED RISKS OF ALLERGIC DISEASE IN CHILDREN. WE FOUND THAT EXPERIMENTAL INTRAUTERINE GROWTH RESTRICTION (IUGR) IN SHEEP REDUCED CUTANEOUS RESPONSES TO ANTIGENS IN PROGENY, DESPITE NORMAL OR ELEVATED IGE RESPONSES. FURTHERMORE, MATERNAL METHYL DONOR SUPPLEMENTATION IN LATE PREGNANCY PARTIALLY REVERSED EFFECTS OF EXPERIMENTAL IUGR, CONSISTENT WITH THE PROPOSAL THAT EPIGENETIC PATHWAYS UNDERLIE SOME BUT NOT ALL EFFECTS OF IUGR ON ALLERGIC SUSCEPTIBILITY. OVINE EXPERIMENTAL ALLERGIC ASTHMA WITH EXACERBATIONS REDUCES RELATIVE FETAL SIZE IN LATE GESTATION, WITH SOME CHANGES IN IMMUNE POPULATIONS IN FETAL THYMUS SUGGESTIVE OF INCREASED ACTIVATION. MATERNAL ALLERGIC ASTHMA IN MICE ALSO PREDISPOSES PROGENY TO ALLERGY DEVELOPMENT. IN CONCLUSION, THESE FINDINGS IN EXPERIMENTAL MODELS PROVIDE DIRECT EVIDENCE THAT A PERTURBED ENVIRONMENT BEFORE BIRTH ALTERS IMMUNE SYSTEM DEVELOPMENT AND POSTNATAL FUNCTION, AND PROVIDE OPPORTUNITIES TO INVESTIGATE UNDERLYING MECHANISMS AND DEVELOP AND EVALUATE INTERVENTIONS. 2017 4 660 29 BLOOD LEVELS OF T-CELL RECEPTOR EXCISION CIRCLES (TRECS) PROVIDE AN INDEX OF EXPOSURE TO TRAUMATIC STRESS IN MICE AND HUMANS. EXPOSURE TO STRESS TRIGGERS BIOLOGICAL CHANGES THROUGHOUT THE BODY. ACCUMULATING EVIDENCE INDICATES THAT ALTERATIONS IN IMMUNE SYSTEM FUNCTION ARE ASSOCIATED WITH THE DEVELOPMENT OF STRESS-ASSOCIATED ILLNESSES SUCH AS MAJOR DEPRESSIVE DISORDER AND POST-TRAUMATIC STRESS DISORDER, INCREASING INTEREST IN IDENTIFYING IMMUNE MARKERS THAT PROVIDE INSIGHT INTO MENTAL HEALTH. RECOMBINATION EVENTS DURING T-CELL RECEPTOR REARRANGEMENT AND T-CELL MATURATION IN THE THYMUS PRODUCE CIRCULAR DNA FRAGMENTS CALLED T-CELL RECEPTOR EXCISION CIRCLES (TRECS) THAT CAN BE UTILIZED AS INDICATORS OF THYMIC FUNCTION AND NUMBERS OF NEWLY EMIGRATING T-CELLS. GIVEN DATA SUGGESTING THAT STRESS AFFECTS THYMUS FUNCTION, WE EXAMINED WHETHER BLOOD LEVELS OF TRECS MIGHT SERVE AS A QUANTITATIVE PERIPHERAL INDEX OF CUMULATIVE STRESS EXPOSURE AND ITS PHYSIOLOGICAL CORRELATES. WE HYPOTHESIZED THAT CHRONIC STRESS EXPOSURE WOULD COMPROMISE THYMUS FUNCTION AND PRODUCE CORRESPONDING DECREASES IN LEVELS OF TRECS. IN MALE MICE, EXPOSURE TO CHRONIC SOCIAL DEFEAT STRESS (CSDS) PRODUCED THYMIC INVOLUTION, ADRENAL HYPERTROPHY, AND DECREASED LEVELS OF TRECS IN BLOOD. EXTENDING THESE STUDIES TO HUMANS REVEALED ROBUST INVERSE CORRELATIONS BETWEEN LEVELS OF CIRCULATING TRECS AND CHILDHOOD EMOTIONAL AND PHYSICAL ABUSE. CELL-TYPE SPECIFIC ANALYSES ALSO REVEALED ASSOCIATIONS BETWEEN TREC LEVELS AND BLOOD CELL COMPOSITION, AS WELL AS CELL-TYPE SPECIFIC METHYLATION CHANGES IN CD4T + AND CD8T + CELLS. ADDITIONALLY, TREC LEVELS CORRELATED WITH EPIGENETIC AGE ACCELERATION, A COMMON BIOMARKER OF STRESS EXPOSURE. OUR FINDINGS DEMONSTRATE ALIGNMENT BETWEEN FINDINGS IN MICE AND HUMANS AND SUGGEST THAT BLOOD-BORNE TRECS ARE A TRANSLATIONALLY-RELEVANT BIOMARKER THAT CORRELATES WITH, AND PROVIDES INSIGHT INTO, THE CUMULATIVE PHYSIOLOGICAL AND IMMUNE-RELATED IMPACTS OF STRESS EXPOSURE IN MAMMALS. 2022 5 3973 27 LONG-TERM BEHAVIORAL AND NEUROENDOCRINE ALTERATIONS FOLLOWING CHRONIC SOCIAL STRESS IN MICE: IMPLICATIONS FOR STRESS-RELATED DISORDERS. THE PERIOD OF ADOLESCENCE IS CHARACTERIZED BY A HIGH VULNERABILITY TO STRESS AND TRAUMA, WHICH MIGHT RESULT IN LONG-LASTING CONSEQUENCES AND AN INCREASED RISK TO DEVELOP PSYCHIATRIC DISORDERS. USING A RECENTLY DEVELOPED MOUSE MODEL FOR CHRONIC SOCIAL STRESS DURING ADOLESCENCE, WE STUDIED PERSISTENT NEUROENDOCRINE AND BEHAVIORAL EFFECTS OF CHRONIC SOCIAL STRESS OBTAINED 12 MONTHS AFTER CESSATION OF THE STRESSOR. AS A REFERENCE, WE INVESTIGATED IMMEDIATE EFFECTS OF CHRONIC STRESS EXPOSURE OBTAINED AT THE END OF THE CHRONIC STRESS PERIOD. IMMEDIATELY AFTER THE 7 WEEK CHRONIC STRESS PERIOD STRESSED ANIMALS SHOW SIGNIFICANTLY INCREASED ADRENAL WEIGHTS, DECREASED THYMUS WEIGHT, INCREASED BASAL CORTICOSTERONE SECRETION AND A FLATTENED CIRCADIAN RHYTHM. FURTHERMORE, STRESSED ANIMALS DISPLAY AN INCREASED ANXIETY-LIKE BEHAVIOR IN THE ELEVATED PLUS MAZE AND THE NOVELTY-INDUCED SUPPRESSION OF FEEDING TEST. HIPPOCAMPAL MINERALOCORTICOID RECEPTOR (MR) AND THE GLUCOCORTICOID RECEPTOR (GR) MRNA LEVELS WERE SIGNIFICANTLY DECREASED. TO INVESTIGATE PERSISTENT CONSEQUENCES OF THIS EARLY STRESSFUL EXPERIENCE, THE SAME PARAMETERS WERE ASSESSED IN AGED MICE 12 MONTHS AFTER THE CESSATION OF THE STRESSOR. INTERESTINGLY, WE STILL FOUND DIFFERENCES BETWEEN FORMERLY STRESSED AND CONTROL MICE IN IMPORTANT STRESS-RELATED PARAMETERS. MR EXPRESSION LEVELS WERE SIGNIFICANTLY LOWER IN STRESSED ANIMALS, SUGGESTING LASTING, POSSIBLY EPIGENETIC ALTERATIONS IN GENE EXPRESSION REGULATION. FURTHERMORE, WE OBSERVED LONG-TERM BEHAVIORAL ALTERATIONS IN ANIMALS STRESSED DURING ADOLESCENCE. THUS, WE COULD DEMONSTRATE THAT CHRONIC STRESS EXPOSURE DURING A CRUCIAL DEVELOPMENTAL TIME PERIOD RESULTS IN LONG-TERM, PERSISTENT EFFECTS ON PHYSIOLOGICAL AND BEHAVIORAL PARAMETERS THROUGHOUT LIFE, WHICH MAY CONTRIBUTE TO AN ENHANCED VULNERABILITY TO STRESS-INDUCED DISEASES. 2008 6 1175 35 CONTRIBUTIONS OF AGE-RELATED THYMIC INVOLUTION TO IMMUNOSENESCENCE AND INFLAMMAGING. IMMUNE SYSTEM AGING IS CHARACTERIZED BY THE PARADOX OF IMMUNOSENESCENCE (INSUFFICIENCY) AND INFLAMMAGING (OVER-REACTION), WHICH INCORPORATE TWO SIDES OF THE SAME COIN, RESULTING IN IMMUNE DISORDER. IMMUNOSENESCENCE REFERS TO DISRUPTION IN THE STRUCTURAL ARCHITECTURE OF IMMUNE ORGANS AND DYSFUNCTION IN IMMUNE RESPONSES, RESULTING FROM BOTH AGED INNATE AND ADAPTIVE IMMUNITY. INFLAMMAGING, DESCRIBED AS A CHRONIC, STERILE, SYSTEMIC INFLAMMATORY CONDITION ASSOCIATED WITH ADVANCED AGE, IS MAINLY ATTRIBUTED TO SOMATIC CELLULAR SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE (SASP) AND AGE-RELATED AUTOIMMUNE PREDISPOSITION. HOWEVER, THE INABILITY TO REDUCE SENESCENT SOMATIC CELLS (SSCS), BECAUSE OF IMMUNOSENESCENCE, EXACERBATES INFLAMMAGING. AGE-RELATED ADAPTIVE IMMUNE SYSTEM DEVIATIONS, PARTICULARLY ALTERED T CELL FUNCTION, ARE DERIVED FROM AGE-RELATED THYMIC ATROPHY OR INVOLUTION, A HALLMARK OF THYMIC AGING. RECENTLY, THERE HAVE BEEN MAJOR DEVELOPMENTS IN UNDERSTANDING HOW AGE-RELATED THYMIC INVOLUTION CONTRIBUTES TO INFLAMMAGING AND IMMUNOSENESCENCE AT THE CELLULAR AND MOLECULAR LEVELS, INCLUDING GENETIC AND EPIGENETIC REGULATION, AS WELL AS DEVELOPMENTS OF MANY POTENTIAL REJUVENATION STRATEGIES. HEREIN, WE DISCUSS THE RESEARCH PROGRESS UNCOVERING HOW AGE-RELATED THYMIC INVOLUTION CONTRIBUTES TO IMMUNOSENESCENCE AND INFLAMMAGING, AS WELL AS THEIR INTERSECTION. WE ALSO DESCRIBE HOW T CELL ADAPTIVE IMMUNITY MEDIATES INFLAMMAGING AND PLAYS A CRUCIAL ROLE IN THE PROGRESSION OF AGE-RELATED NEUROLOGICAL AND CARDIOVASCULAR DISEASES, AS WELL AS CANCER. WE THEN BRIEFLY OUTLINE THE UNDERLYING CELLULAR AND MOLECULAR MECHANISMS OF AGE-RELATED THYMIC INVOLUTION, AND FINALLY SUMMARIZE POTENTIAL REJUVENATION STRATEGIES TO RESTORE AGED THYMIC FUNCTION. 2020 7 5414 35 REGULATION OF CD8(+) T MEMORY AND EXHAUSTION BY THE MTOR SIGNALS. CD8(+) T CELLS ARE THE KEY EXECUTIONERS OF THE ADAPTIVE IMMUNE ARM, WHICH MEDIATES ANTITUMOR AND ANTIVIRAL IMMUNITY. NAIVE CD8(+) T CELLS DEVELOP IN THE THYMUS AND ARE QUICKLY ACTIVATED IN THE PERIPHERY AFTER ENCOUNTERING A COGNATE ANTIGEN, WHICH INDUCES THESE CELLS TO PROLIFERATE AND DIFFERENTIATE INTO EFFECTOR CELLS THAT FIGHT THE INITIAL INFECTION. SIMULTANEOUSLY, A FRACTION OF THESE CELLS BECOME LONG-LIVED MEMORY CD8(+) T CELLS THAT COMBAT FUTURE INFECTIONS. NOTABLY, THE GENERATION AND MAINTENANCE OF MEMORY CELLS IS PROFOUNDLY AFFECTED BY VARIOUS IN VIVO CONDITIONS, SUCH AS THE MODE OF PRIMARY ACTIVATION (E.G., ACUTE VS. CHRONIC IMMUNIZATION) OR FLUCTUATIONS IN HOST METABOLIC, INFLAMMATORY, OR AGING FACTORS. THEREFORE, MANY T CELLS MAY BE LOST OR BECOME EXHAUSTED AND NO LONGER FUNCTIONAL. COMPLICATED INTRACELLULAR SIGNALING PATHWAYS, TRANSCRIPTION FACTORS, EPIGENETIC MODIFICATIONS, AND METABOLIC PROCESSES ARE INVOLVED IN THIS PROCESS. THEREFORE, UNDERSTANDING THE CELLULAR AND MOLECULAR BASIS FOR THE GENERATION AND FATE OF MEMORY AND EXHAUSTED CD8(+) CELLS IS CENTRAL FOR HARNESSING CELLULAR IMMUNITY. IN THIS REVIEW, WE FOCUS ON MAMMALIAN TARGET OF RAPAMYCIN (MTOR), PARTICULARLY SIGNALING MEDIATED BY MTOR COMPLEX (MTORC) 2 IN MEMORY AND EXHAUSTED CD8(+) T CELLS AT THE MOLECULAR LEVEL. 2023 8 5896 42 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 9 4975 32 PATHOPHYSIOLOGICAL MECHANISMS OF AUTOIMMUNITY. AUTOIMMUNE DISEASES (AIDS) ARE CHRONIC DISORDERS CHARACTERIZED BY INFLAMMATORY REACTIONS AGAINST SELF-ANTIGENS THAT CAN BE EITHER SYSTEMIC OR ORGAN SPECIFIC. AIDS CAN DIFFER IN THEIR EPIDEMIOLOGIC FEATURES AND CLINICAL PRESENTATIONS, YET ALL SHARE A REMARKABLE COMPLEXITY. AIDS RESULT FROM AN INTERPLAY OF GENETIC AND EPIGENETIC FACTORS WITH ENVIRONMENTAL COMPONENTS THAT ARE ASSOCIATED WITH IMBALANCES IN THE IMMUNE SYSTEM. MANY OF THE PATHOGENIC MECHANISMS OF AIDS ARE ALSO IMPLICATED IN MYASTHENIA GRAVIS (MG), AN AID IN WHICH INFLAMMATION OF THE THYMUS LEADS TO A NEUROMUSCULAR DISORDER. OUR GOAL HERE IS TO HIGHLIGHT THE SIMILARITIES AND DIFFERENCES BETWEEN MG AND OTHER AIDS BY REVIEWING THE COMMON TRANSCRIPTOME SIGNATURES AND THE DEVELOPMENT OF GERMINAL CENTERS AND BY DISCUSSING SOME UNRESOLVED QUESTIONS ABOUT AUTOIMMUNE MECHANISMS. THIS REVIEW WILL PROPOSE HYPOTHESES TO EXPLAIN THE ORIGIN OF REGULATORY T (T(REG) ) CELL DEFECTS AND THE CAUSES OF CHRONICITY AND SPECIFICITY OF AIDS. 2018 10 235 17 ADDING FUEL TO THE FIRE: THE IMPACT OF STRESS ON THE AGEING BRAIN. BOTH AGEING AND CHRONIC STRESS ARE ASSOCIATED WITH ALTERED BRAIN PLASTICITY, DYSREGULATION OF THE IMMUNE SYSTEM, AND AN INCREASED RISK OF DEVELOPING BRAIN DISORDERS; ALL OF WHICH HAVE CONSEQUENCES FOR COGNITIVE AND EMOTIONAL PROCESSING. HERE WE EXAMINE THE SIMILARITIES BETWEEN BEHAVIOURAL CHANGES DURING AGEING AND STRESS ALTERED BEHAVIOURS (ANXIETY, DEPRESSIVE-LIKE BEHAVIOUR, COGNITION, AND SOCIABILITY) IN RODENTS AND HUMANS. THE MOLECULAR MECHANISMS HYPOTHESISED TO MEDIATE AGE-RELATED CHANGES IN BRAIN FUNCTION INCLUDING DYSFUNCTION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS, DYSREGULATION OF NEUROTRANSMISSION AND NEUROTROPHIC FACTOR SIGNALLING, INCREASED INFLAMMATORY STATE, GENETIC AND EPIGENETIC CHANGES, OXIDATIVE STRESS, METABOLIC CHANGES, AND CHANGES IN THE MICROBIOTA-GUT-BRAIN AXIS ARE DISCUSSED. FINALLY, WE EXPLORE HOW THE ALREADY STRESSED AGED BRAIN PSYCHOLOGICALLY AND PHYSIOLOGICALLY RESPONDS TO EXTERNAL STRESSORS. 2015 11 23 36 60 YEARS OF NEUROENDOCRINOLOGY: REDEFINING NEUROENDOCRINOLOGY: STRESS, SEX AND COGNITIVE AND EMOTIONAL REGULATION. THE DISCOVERY OF STEROID HORMONE RECEPTORS IN BRAIN REGIONS THAT MEDIATE EVERY ASPECT OF BRAIN FUNCTION HAS BROADENED THE DEFINITION OF 'NEUROENDOCRINOLOGY' TO INCLUDE THE RECIPROCAL COMMUNICATION BETWEEN THE BRAIN AND THE BODY VIA HORMONAL AND NEURAL PATHWAYS. THE BRAIN IS THE CENTRAL ORGAN OF STRESS AND ADAPTATION TO STRESS BECAUSE IT PERCEIVES AND DETERMINES WHAT IS THREATENING, AS WELL AS THE BEHAVIORAL AND PHYSIOLOGICAL RESPONSES TO THE STRESSOR. THE ADULT AND DEVELOPING BRAIN POSSESS REMARKABLE STRUCTURAL AND FUNCTIONAL PLASTICITY IN RESPONSE TO STRESS, INCLUDING NEURONAL REPLACEMENT, DENDRITIC REMODELING, AND SYNAPSE TURNOVER. STRESS CAUSES AN IMBALANCE OF NEURAL CIRCUITRY SUBSERVING COGNITION, DECISION-MAKING, ANXIETY AND MOOD THAT CAN ALTER EXPRESSION OF THOSE BEHAVIORS AND BEHAVIORAL STATES. THIS IMBALANCE, IN TURN, AFFECTS SYSTEMIC PHYSIOLOGY VIA NEUROENDOCRINE, AUTONOMIC, IMMUNE AND METABOLIC MEDIATORS. IN THE SHORT TERM, AS FOR INCREASED FEARFUL VIGILANCE AND ANXIETY IN A THREATENING ENVIRONMENT, THESE CHANGES MAY BE ADAPTIVE. BUT, IF THE DANGER PASSES AND THE BEHAVIORAL STATE PERSISTS ALONG WITH THE CHANGES IN NEURAL CIRCUITRY, SUCH MALADAPTATION MAY NEED INTERVENTION WITH A COMBINATION OF PHARMACOLOGICAL AND BEHAVIORAL THERAPIES, AS IS THE CASE FOR CHRONIC ANXIETY AND DEPRESSION. THERE ARE IMPORTANT SEX DIFFERENCES IN THE BRAIN RESPONSES TO STRESSORS THAT ARE IN URGENT NEED OF FURTHER EXPLORATION. MOREOVER, ADVERSE EARLY-LIFE EXPERIENCE, INTERACTING WITH ALLELES OF CERTAIN GENES, PRODUCE LASTING EFFECTS ON BRAIN AND BODY OVER THE LIFE-COURSE VIA EPIGENETIC MECHANISMS. WHILE PREVENTION IS MOST IMPORTANT, THE PLASTICITY OF THE BRAIN GIVES HOPE FOR THERAPIES THAT TAKE INTO CONSIDERATION BRAIN-BODY INTERACTIONS. 2015 12 6522 41 TRANSCRIPTIONAL AND EPIGENETIC REGULATION OF T CELL HYPORESPONSIVENESS. NAIVE CD8(+) T CELLS DIFFERENTIATE INTO EFFECTOR AND MEMORY CYTOLYTIC T CELLS (CTLS) DURING AN ACUTE INFECTION. IN CONTRAST, IN SCENARIOS OF PERSISTENT ANTIGEN STIMULATION, SUCH AS CHRONIC INFECTIONS AND CANCER, ANTIGEN-SPECIFIC CTLS SHOW A GRADUAL DECREASE IN EFFECTOR FUNCTION, A PHENOMENON THAT HAS BEEN TERMED CD8(+) T CELL "EXHAUSTION" OR "DYSFUNCTION." ANOTHER HYPORESPONSIVE STATE, TERMED "ANERGY", IS OBSERVED WHEN T CELLS ARE ACTIVATED IN THE ABSENCE OF POSITIVE COSTIMULATORY SIGNALS. AMONG THE MANY NEGATIVE REGULATORS INDUCED IN HYPORESPONSIVE T CELLS ARE INHIBITORY CELL-SURFACE RECEPTORS, SUCH AS PD-1, LAG-3, CTLA-4, AND TIM-3; "CHECKPOINT BLOCKADE" THERAPIES THAT INVOLVE TREATMENT OF PATIENTS WITH CANCER WITH BLOCKING ANTIBODIES TO THOSE RECEPTORS SHOW CONSIDERABLE PROMISE IN THE CLINIC BECAUSE THE BLOCKING ANTIBODIES CAN MITIGATE HYPORESPONSIVENESS AND PROMOTE TUMOR REJECTION. IN THIS REVIEW, WE DESCRIBE RECENT ADVANCES IN OUR MOLECULAR UNDERSTANDING OF THESE HYPORESPONSIVE STATES. WE REVIEW EVIDENCE FOR THE INVOLVEMENT OF DIVERSE TRANSCRIPTION FACTORS, METABOLIC PROGRAMS, AND CHROMATIN ACCESSIBILITY CHANGES IN HYPORESPONSIVE T CELLS, AND WE DISCUSS HOW CHECKPOINT BLOCKADE THERAPIES AFFECT THE MOLECULAR PROGRAM OF CD8(+) T CELL EXHAUSTION. 2017 13 4178 26 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 3092 28 GENOMIC AND EPIGENOMIC MECHANISMS OF GLUCOCORTICOIDS IN THE BRAIN. FOLLOWING THE DISCOVERY OF GLUCOCORTICOID RECEPTORS IN THE HIPPOCAMPUS AND OTHER BRAIN REGIONS, RESEARCH HAS FOCUSED ON UNDERSTANDING THE EFFECTS OF GLUCOCORTICOIDS IN THE BRAIN AND THEIR ROLE IN REGULATING EMOTION AND COGNITION. GLUCOCORTICOIDS ARE ESSENTIAL FOR ADAPTATION TO STRESSORS (ALLOSTASIS) AND IN MALADAPTATION RESULTING FROM ALLOSTATIC LOAD AND OVERLOAD. ALLOSTATIC OVERLOAD, WHICH CAN OCCUR DURING CHRONIC STRESS, CAN RESHAPE THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS THROUGH EPIGENETIC MODIFICATION OF GENES IN THE HIPPOCAMPUS, HYPOTHALAMUS AND OTHER STRESS-RESPONSIVE BRAIN REGIONS. GLUCOCORTICOIDS EXERT THEIR EFFECTS ON THE BRAIN THROUGH GENOMIC MECHANISMS THAT INVOLVE BOTH GLUCOCORTICOID RECEPTORS AND MINERALOCORTICOID RECEPTORS DIRECTLY BINDING TO DNA, AS WELL AS BY NON-GENOMIC MECHANISMS. FURTHERMORE, GLUCOCORTICOIDS SYNERGIZE BOTH GENOMICALLY AND NON-GENOMICALLY WITH NEUROTRANSMITTERS, NEUROTROPHIC FACTORS, SEX HORMONES AND OTHER STRESS MEDIATORS TO SHAPE AN ORGANISM'S PRESENT AND FUTURE RESPONSES TO A STRESSFUL ENVIRONMENT. HERE, WE DISCUSS THE MECHANISMS OF GLUCOCORTICOID ACTION IN THE BRAIN AND REVIEW HOW GLUCOCORTICOIDS INTERACT WITH STRESS MEDIATORS IN THE CONTEXT OF ALLOSTASIS, ALLOSTATIC LOAD AND STRESS-INDUCED NEUROPLASTICITY. 2017 15 3463 26 HYPOTHALAMIC-PITUITARY-ADRENAL AND HYPOTHALAMIC-PITUITARY-GONADAL AXES: SEX DIFFERENCES IN REGULATION OF STRESS RESPONSIVITY. GONADAL HORMONES PLAY A KEY ROLE IN THE ESTABLISHMENT, ACTIVATION, AND REGULATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS. BY INFLUENCING THE RESPONSE AND SENSITIVITY TO RELEASING FACTORS, NEUROTRANSMITTERS, AND HORMONES, GONADAL STEROIDS HELP ORCHESTRATE THE GAIN OF THE HPA AXIS TO FINE-TUNE THE LEVELS OF STRESS HORMONES IN THE GENERAL CIRCULATION. FROM EARLY LIFE TO ADULTHOOD, GONADAL STEROIDS CAN DIFFERENTIALLY AFFECT THE HPA AXIS, RESULTING IN SEX DIFFERENCES IN THE RESPONSIVITY OF THIS AXIS. THE HPA AXIS INFLUENCES MANY PHYSIOLOGICAL FUNCTIONS MAKING AN ORGANISM'S RESPONSE TO CHANGES IN THE ENVIRONMENT APPROPRIATE FOR ITS REPRODUCTIVE STATUS. ALTHOUGH THE ACUTE HPA RESPONSE TO STRESSORS IS A BENEFICIAL RESPONSE, CONSTANT ACTIVATION OF THIS CIRCUITRY BY CHRONIC OR TRAUMATIC STRESSFUL EPISODES MAY LEAD TO A DYSREGULATION OF THE HPA AXIS AND CAUSE PATHOLOGY. COMPARED TO MALES, FEMALE MICE AND RATS SHOW A MORE ROBUST HPA AXIS RESPONSE, AS A RESULT OF CIRCULATING ESTRADIOL LEVELS WHICH ELEVATE STRESS HORMONE LEVELS DURING NON-THREATENING SITUATIONS, AND DURING AND AFTER STRESSORS. FLUCTUATING LEVELS OF GONADAL STEROIDS IN FEMALES ACROSS THE ESTROUS CYCLE ARE A MAJOR FACTOR CONTRIBUTING TO SEX DIFFERENCES IN THE ROBUSTNESS OF HPA ACTIVITY IN FEMALES COMPARED TO MALES. MOREOVER, GONADAL STEROIDS MAY ALSO CONTRIBUTE TO EPIGENETIC AND ORGANIZATIONAL INFLUENCES ON THE HPA AXIS EVEN BEFORE PUBERTY. CORRESPONDINGLY, CROSSTALK BETWEEN THE HYPOTHALAMIC-PITUITARY-GONADAL (HPG) AND HPA AXES COULD LEAD TO ABNORMALITIES OF STRESS RESPONSES. IN HUMANS, A DYSREGULATED STRESS RESPONSE IS ONE OF THE MOST COMMON SYMPTOMS SEEN ACROSS MANY NEUROPSYCHIATRIC DISORDERS, AND AS A RESULT, SUCH INTERACTIONS MAY EXACERBATE PERIPHERAL PATHOLOGIES. IN THIS REVIEW, WE DISCUSS THE HPA AND HPG AXES AND REVIEW HOW GONADAL STEROIDS INTERACT WITH THE HPA AXIS TO REGULATE THE STRESS CIRCUITRY DURING ALL STAGES IN LIFE. 2017 16 4186 28 METABOLIC AND EPIGENETIC REGULATION OF T-CELL EXHAUSTION. CURRENT IMMUNOTHERAPIES YIELD REMARKABLE CLINICAL OUTCOMES BY BOOSTING THE POWER OF HOST IMMUNITY IN CANCER CELL ELIMINATION AND VIRAL CLEARANCE. HOWEVER, AFTER PROLONGED ANTIGEN EXPOSURE, CD8(+) T CELLS DIFFERENTIATE INTO A SPECIAL DIFFERENTIATION STATE KNOWN AS T-CELL EXHAUSTION, WHICH POSES ONE OF THE MAJOR HURDLES TO ANTIVIRAL AND ANTITUMOR IMMUNITY DURING CHRONIC VIRAL INFECTION AND TUMOUR DEVELOPMENT. GROWING EVIDENCE INDICATES THAT EXHAUSTED T CELLS UNDERGO METABOLIC INSUFFICIENCY WITH ALTERED SIGNALLING CASCADES AND EPIGENETIC LANDSCAPES, WHICH DAMPEN EFFECTOR IMMUNITY AND CAUSE POOR RESPONSIVENESS TO IMMUNE-CHECKPOINT-BLOCKADE THERAPIES. HOW METABOLIC STRESS AFFECTS T-CELL EXHAUSTION REMAINS UNCLEAR; THEREFORE, IN THIS REVIEW, WE SUMMARIZE CURRENT KNOWLEDGE OF HOW T-CELL EXHAUSTION OCCURS, AND DISCUSS HOW METABOLIC INSUFFICIENCY AND PROLONGED STRESS RESPONSES MAY AFFECT SIGNALLING CASCADES AND EPIGENETIC REPROGRAMMING, THUS LOCKING T CELLS INTO AN EXHAUSTED STATE VIA SPECIALIZED DIFFERENTIATION PROGRAMMING. 2020 17 5812 33 STRESS AND ANXIETY: STRUCTURAL PLASTICITY AND EPIGENETIC REGULATION AS A CONSEQUENCE OF STRESS. THE BRAIN IS THE CENTRAL ORGAN OF STRESS AND ADAPTATION TO STRESS BECAUSE IT PERCEIVES AND DETERMINES WHAT IS THREATENING, AS WELL AS THE BEHAVIORAL AND PHYSIOLOGICAL RESPONSES TO THE STRESSOR. THE ADULT, AS WELL AS DEVELOPING BRAIN, POSSESS A REMARKABLE ABILITY TO SHOW REVERSIBLE STRUCTURAL AND FUNCTIONAL PLASTICITY IN RESPONSE TO STRESSFUL AND OTHER EXPERIENCES, INCLUDING NEURONAL REPLACEMENT, DENDRITIC REMODELING, AND SYNAPSE TURNOVER. THIS IS PARTICULARLY EVIDENT IN THE HIPPOCAMPUS, WHERE ALL THREE TYPES OF STRUCTURAL PLASTICITY HAVE BEEN RECOGNIZED AND INVESTIGATED, USING A COMBINATION OF MORPHOLOGICAL, MOLECULAR, PHARMACOLOGICAL, ELECTROPHYSIOLOGICAL AND BEHAVIORAL APPROACHES. THE AMYGDALA AND THE PREFRONTAL CORTEX, BRAIN REGIONS INVOLVED IN ANXIETY AND FEAR, MOOD, COGNITIVE FUNCTION AND BEHAVIORAL CONTROL, ALSO SHOW STRUCTURAL PLASTICITY. ACUTE AND CHRONIC STRESS CAUSE AN IMBALANCE OF NEURAL CIRCUITRY SUBSERVING COGNITION, DECISION MAKING, ANXIETY AND MOOD THAT CAN INCREASE OR DECREASE EXPRESSION OF THOSE BEHAVIORS AND BEHAVIORAL STATES. IN THE SHORT TERM, SUCH AS FOR INCREASED FEARFUL VIGILANCE AND ANXIETY IN A THREATENING ENVIRONMENT, THESE CHANGES MAY BE ADAPTIVE; BUT, IF THE DANGER PASSES AND THE BEHAVIORAL STATE PERSISTS ALONG WITH THE CHANGES IN NEURAL CIRCUITRY, SUCH MALADAPTATION MAY NEED INTERVENTION WITH A COMBINATION OF PHARMACOLOGICAL AND BEHAVIORAL THERAPIES, AS IS THE CASE FOR CHRONIC OR MOOD ANXIETY DISORDERS. WE SHALL REVIEW CELLULAR AND MOLECULAR MECHANISMS, AS WELL AS RECENT WORK ON INDIVIDUAL DIFFERENCES IN ANXIETY-LIKE BEHAVIOR AND ALSO DEVELOPMENTAL INFLUENCES THAT BIAS HOW THE BRAIN RESPONDS TO STRESSORS. FINALLY, WE SUGGEST THAT SUCH AN APPROACH NEEDS TO BE EXTENDED TO OTHER BRAIN AREAS THAT ARE ALSO INVOLVED IN ANXIETY AND MOOD. THIS ARTICLE IS PART OF A SPECIAL ISSUE ENTITLED 'ANXIETY AND DEPRESSION'. 2012 18 3313 28 HIPPOCAMPAL BDNF IN PHYSIOLOGICAL CONDITIONS AND SOCIAL ISOLATION. EXPOSURE OF AN ORGANISM TO CHRONIC PSYCHOSOCIAL STRESS MAY AFFECT BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) EXPRESSION THAT HAS BEEN IMPLICATED IN THE ETIOLOGY OF PSYCHIATRIC DISORDERS, SUCH AS DEPRESSION. GIVEN THAT DEPRESSION IN HUMANS HAS BEEN LINKED WITH SOCIAL STRESS, THE CHRONIC SOCIAL STRESS PARADIGMS FOR MODELING PSYCHIATRIC DISORDERS IN ANIMALS HAVE THUS BEEN DEVELOPED. CHRONIC SOCIAL ISOLATION IN ANIMAL MODELS GENERALLY CAUSES CHANGES IN HYPOTHALAMIC-PITUITARY-ADRENAL AXIS FUNCTIONING, ASSOCIATED WITH ANXIETY- AND DEPRESSIVE-LIKE BEHAVIORS. ALSO, THIS CHRONIC STRESS CAUSES DOWNREGULATION OF BDNF PROTEIN AND MRNA IN THE HIPPOCAMPUS, A STRESS-SENSITIVE BRAIN REGION CLOSELY RELATED TO THE PATHOPHYSIOLOGY OF DEPRESSION. IN THIS REVIEW, WE DISCUSS THE CURRENT KNOWLEDGE REGARDING THE STRUCTURE, FUNCTION, INTRACELLULAR SIGNALING, INTER-INDIVIDUAL DIFFERENCES AND EPIGENETIC REGULATION OF BDNF IN BOTH PHYSIOLOGICAL CONDITIONS AND DEPRESSION AND CHANGES IN CORTICOSTERONE LEVELS, AS A MARKER OF STRESS RESPONSE. SINCE BDNF LEVELS ARE AGE DEPENDENT IN HUMANS AND RODENTS, THIS REVIEW WILL ALSO HIGHLIGHT THE EFFECTS OF ADOLESCENT AND ADULT CHRONIC SOCIAL ISOLATION MODELS OF BOTH GENDERS ON THE BDNF EXPRESSION. 2017 19 5662 31 SEXUAL DIMORPHISM IN GLUCOCORTICOID STRESS RESPONSE. CHRONIC STRESS IS ENCOUNTERED IN OUR EVERYDAY LIFE AND IS THOUGHT TO CONTRIBUTE TO A NUMBER OF DISEASES. MANY OF THESE STRESS-RELATED DISORDERS DISPLAY A SEX BIAS. BECAUSE GLUCOCORTICOID HORMONES ARE THE MAIN BIOLOGICAL MEDIATOR OF CHRONIC STRESS, RESEARCHERS HAVE BEEN INTERESTED IN UNDERSTANDING THE SEXUAL DIMORPHISM IN GLUCOCORTICOID STRESS RESPONSE TO BETTER EXPLAIN THE SEX BIAS IN STRESS-RELATED DISEASES. ALTHOUGH NOT YET DEMONSTRATED FOR GLUCOCORTICOID REGULATION, SEX CHROMOSOMES DO INFLUENCE SEX-SPECIFIC BIOLOGY AS SOON AS CONCEPTION. THEN A TRANSIENT RISE IN TESTOSTERONE START TO SHAPE THE MALE BRAIN DURING THE PRENATAL PERIOD DIFFERENTLY TO THE FEMALE BRAIN. THESE ORGANIZATIONAL EFFECTS ARE COMPLETED JUST BEFORE PUBERTY. THE CEREBRAL REGIONS IMPLICATED IN GLUCOCORTICOID REGULATION AT REST AND AFTER STRESS ARE THEREBY IMPACTED IN A SEX-SPECIFIC MANNER. AFTER PUBERTY, THE HIGH LEVELS OF ALL GONADAL HORMONES WILL INTERACT WITH GLUCOCORTICOID HORMONES IN SPECIFIC CROSSTALK THROUGH THEIR RESPECTIVE NUCLEAR RECEPTORS. IN ADDITION, STRESS OCCURRING EARLY IN LIFE, IN PARTICULAR DURING THE PRENATAL PERIOD AND IN ADOLESCENCE WILL PRIME IN THE LONG-TERM GLUCOCORTICOID STRESS RESPONSE THROUGH EPIGENETIC MECHANISMS, AGAIN IN A SEX-SPECIFIC MANNER. ALTOGETHER, VARIOUS MOLECULAR MECHANISMS EXPLAIN SEX-SPECIFIC GLUCOCORTICOID STRESS RESPONSES THAT DO NOT EXCLUDE IMPORTANT GENDER EFFECTS IN HUMANS. 2021 20 233 29 ADAPTIVE T CELL TUNING IN IMMUNE REGULATION AND IMMUNOTHERAPY OF AUTOIMMUNE DISEASES(?). LYMPHOCYTE RECEPTORS CONFER ANTIGEN SPECIFICITY ON THE ADAPTIVE IMMUNE RESPONSE. INCREASING EVIDENCE POINTS TO THE ROLE OF ADAPTIVE TUNING PARTICULARLY AMONGST CD4(+) T CELL RESPONSES. THIS REVIEW SUMMARISES HOW T CELL TUNING IMPACTS ON CRITICALLY IMPORTANT ASPECTS OF IMMUNE REGULATION INCLUDING THYMIC SELECTION, THE IMMUNE RESPONSE TO CHRONIC ANTIGEN EXPOSURE AND ANTIGEN-SPECIFIC IMMUNOTHERAPY OF AUTOIMMUNE CONDITIONS. RECENT WORK HAS REVEALED A NOVEL MECHANISM FOR T CELL ANERGY AND REGULATORY TYPE 1 T CELL DIFFERENTIATION THROUGH A LIMITATION OF T CELL RECEPTOR MEDIATED SIGNALLING COMBINED WITH EPIGENETIC PRIMING OF TOLERANCE ASSOCIATED GENES. 2022