2023
1025 Tumor-specific CD8+ T cells epigenetically licensed by IL-7R are critical for anti-tumor immunity in melanoma
Micevic G, Daniels A, Flem-Karlsen K, Park K, Talty R, McGeary M, Mirza H, Blackburn H, Sefik E, Cheung J, Hornick N, Aizenbud L, Joshi N, Kluger H, Iwasaki A, Bosenberg M, Flavell R. 1025 Tumor-specific CD8+ T cells epigenetically licensed by IL-7R are critical for anti-tumor immunity in melanoma. 2023, a1133-a1133. DOI: 10.1136/jitc-2023-sitc2023.1025.Peer-Reviewed Original ResearchIL-6 trans-signaling in a humanized mouse model of scleroderma
Odell I, Agrawal K, Sefik E, Odell A, Caves E, Kirkiles-Smith N, Horsley V, Hinchcliff M, Pober J, Kluger Y, Flavell R. IL-6 trans-signaling in a humanized mouse model of scleroderma. Proceedings Of The National Academy Of Sciences Of The United States Of America 2023, 120: e2306965120. PMID: 37669366, PMCID: PMC10500188, DOI: 10.1073/pnas.2306965120.Peer-Reviewed Original ResearchConceptsBone marrow-derived immune cellsIL-6Human hematopoietic stem cellsImmune cellsT cellsScleroderma skinSoluble IL-6 receptorCD8 T cellsHumanized mouse modelPathogenesis of sclerodermaMesenchymal cellsFibroblast-derived IL-6IL-6 receptorIL-6 signalingT cell activationHuman IL-6Human T cellsExpression of collagenFibrosis improvementPansclerotic morpheaHuman endothelial cellsHumanized miceReduced markersSkin graftsHuman CD4IL-7R licenses a population of epigenetically poised memory CD8+ T cells with superior antitumor efficacy that are critical for melanoma memory
Micevic G, Daniels A, Flem-Karlsen K, Park K, Talty R, McGeary M, Mirza H, Blackburn H, Sefik E, Cheung J, Hornick N, Aizenbud L, Joshi N, Kluger H, Iwasaki A, Bosenberg M, Flavell R. IL-7R licenses a population of epigenetically poised memory CD8+ T cells with superior antitumor efficacy that are critical for melanoma memory. Proceedings Of The National Academy Of Sciences Of The United States Of America 2023, 120: e2304319120. PMID: 37459511, PMCID: PMC10372654, DOI: 10.1073/pnas.2304319120.Peer-Reviewed Original ResearchConceptsIL-7R expressionT cellsIL-7RAntitumor memorySuperior antitumor efficacyCell-based therapiesTumor-specific T cellsAntigen-specific T cellsAntitumor efficacyPowerful antitumor immune responseMarkers of exhaustionTumor-specific CD8Antitumor immune responseIndependent prognostic factorAntitumor immune memoryMemory T cellsMajor risk factorSuperior antitumor activityFunctional CD8Memory CD8Prognostic factorsSurgical resectionAdvanced melanomaLymph nodesNaive miceRegulatory T cells in the face of the intestinal microbiota
Ramanan D, Pratama A, Zhu Y, Venezia O, Sassone-Corsi M, Chowdhary K, Galván-Peña S, Sefik E, Brown C, Gélineau A, Mathis D, Benoist C. Regulatory T cells in the face of the intestinal microbiota. Nature Reviews Immunology 2023, 23: 749-762. PMID: 37316560, DOI: 10.1038/s41577-023-00890-w.Peer-Reviewed Original ResearchA Treg-specific long noncoding RNA maintains immune-metabolic homeostasis in aging liver
Ding C, Yu Z, Sefik E, Zhou J, Kaffe E, Wang G, Li B, Flavell R, Hu W, Ye Y, Li H. A Treg-specific long noncoding RNA maintains immune-metabolic homeostasis in aging liver. Nature Aging 2023, 3: 813-828. PMID: 37277640, DOI: 10.1038/s43587-023-00428-8.Peer-Reviewed Original ResearchConceptsAged miceLiver diseaseLiver microenvironmentAge-related liver diseasesYin Yang 1Liver immune microenvironmentRegulatory T cellsTreg-specific deletionPotential therapeutic targetMitochondrial functionYang 1Treg apoptosisTreg homeostasisTreg cellsTreg functionImmune microenvironmentLiver fibrosisMetabolic dysfunctionOptimal mitochondrial functionYoung miceT cellsLiver cancerTherapeutic targetAged liverLong noncoding RNA
2022
RNA m6A demethylase ALKBH5 regulates the development of γδ T cells
Ding C, Xu H, Yu Z, Roulis M, Qu R, Zhou J, Oh J, Crawford J, Gao Y, Jackson R, Sefik E, Li S, Wei Z, Skadow M, Yin Z, Ouyang X, Wang L, Zou Q, Su B, Hu W, Flavell RA, Li HB. RNA m6A demethylase ALKBH5 regulates the development of γδ T cells. Proceedings Of The National Academy Of Sciences Of The United States Of America 2022, 119: e2203318119. PMID: 35939687, PMCID: PMC9388086, DOI: 10.1073/pnas.2203318119.Peer-Reviewed Original ResearchConceptsDemethylase ALKBH5Messenger RNAΓδ T cellsΓδ T cell biologyCommon posttranscriptional modificationΓδ T cell developmentT cell biologyT cell developmentCell precursorsT cell precursorsMammalian cellsRNA modificationsPosttranscriptional modificationsTissue homeostasisCell biologyT cellsTarget genesCheckpoint roleCell developmentM6A demethylase ALKBH5ALKBH5Γδ T-cell originΓδ T cell repertoireCell populationsEarly development
2020
Tissue-resident memory T cell reactivation by diverse antigen-presenting cells imparts distinct functional responses
Low JS, Farsakoglu Y, Vesely M, Sefik E, Kelly JB, Harman CCD, Jackson R, Shyer JA, Jiang X, Cauley LS, Flavell RA, Kaech SM. Tissue-resident memory T cell reactivation by diverse antigen-presenting cells imparts distinct functional responses. Journal Of Experimental Medicine 2020, 217: e20192291. PMID: 32525985, PMCID: PMC7398161, DOI: 10.1084/jem.20192291.Peer-Reviewed Original ResearchConceptsMemory T cellsT cellsLung CD8TRM cellsTissue-resident memory T cellsLong-term protective immunityT cell reactivationCell reactivationPortal of infectionCell functional responsesMemory CD8Protective immunityEffector responsesLymphoid organsCD8Distinct functional responsesFunctional responseReactivationCellsAPCActivation kineticsCritical roleResponseInfectionImmunityAn Immunologic Mode of Multigenerational Transmission Governs a Gut Treg Setpoint
Ramanan D, Sefik E, Galván-Peña S, Wu M, Yang L, Yang Z, Kostic A, Golovkina T, Kasper D, Mathis D, Benoist C. An Immunologic Mode of Multigenerational Transmission Governs a Gut Treg Setpoint. Cell 2020, 181: 1276-1290.e13. PMID: 32402238, PMCID: PMC7393667, DOI: 10.1016/j.cell.2020.04.030.Peer-Reviewed Original ResearchConceptsDouble-negative feedback loopTreg proportionImmunological modeGut immune responseGut commensalsControlling gut inflammationSpecies levelInbred mouse strainsMulti-generational transmissionTreg-dependent mannerCellular perturbationsRegulatory T cellsDisease susceptibilityNon-epigeneticMaternal transmissionInflammatory disease susceptibilityNon-geneticGut inflammationT cellsGenetic tuningMouse strainsImmune responseMultiple generationsImmune systemFeedback loop
2019
Indiscriminate nature of lung resident CD8+ TRM cells reactivation and their varied reactivation profiles
LOW J, Amezcua C, Sefik E, Harman C, Jackson R, Jiang X, Kelly J, Cauley L, Flavell R, Kaech S. Indiscriminate nature of lung resident CD8+ TRM cells reactivation and their varied reactivation profiles. The Journal Of Immunology 2019, 202: 129.9-129.9. DOI: 10.4049/jimmunol.202.supp.129.9.Peer-Reviewed Original ResearchAntigen-presenting cellsTRM cellsCell reactivationTissue-resident memory cellsLong-term protective immunityLung-resident CD8Resident memory cellsKinetics of CD8Portal of infectionAbstract CD8Memory CD8Bystander activationInfluenza infectionProtective immunityResident CD8Heterologous immunityCD8T cellsPeripheral tissuesAnatomical locationReactivation profileInfectionReactivation kineticsImmediate protectionImmunity
2015
Individual intestinal symbionts induce a distinct population of RORγ+ regulatory T cells
Sefik E, Geva-Zatorsky N, Oh S, Konnikova L, Zemmour D, McGuire AM, Burzyn D, Ortiz-Lopez A, Lobera M, Yang J, Ghosh S, Earl A, Snapper SB, Jupp R, Kasper D, Mathis D, Benoist C. Individual intestinal symbionts induce a distinct population of RORγ+ regulatory T cells. Science 2015, 349: 993-997. PMID: 26272906, PMCID: PMC4700932, DOI: 10.1126/science.aaa9420.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBacteriaBacteroidetesColitis, UlcerativeColonForkhead Transcription FactorsHomeostasisHumansImmunity, MucosalIntestinal MucosaMice, Inbred C57BLMicrobiotaNuclear Receptor Subfamily 1, Group F, Member 3SymbiosisTh17 CellsT-Lymphocyte SubsetsT-Lymphocytes, RegulatoryTranscription, GeneticTranscriptomeConceptsRegulatory T cellsImmuno-inflammatory responseT helper 17 (Th17) cell differentiationTranscription factor Foxp3Important effector moleculeRegulatory cellsHuman gut microbiotaFactor Foxp3T cellsRelated cell typesGut microbiotaMouse colonRORγSymbiotic membersIntestinal symbiontsFoxp3Tissue homeostasisEffector moleculesCell differentiationCell typesDistinct populationsCellsDifferent outcomesInflammation
2014
Treg Cells Expressing the Coinhibitory Molecule TIGIT Selectively Inhibit Proinflammatory Th1 and Th17 Cell Responses
Joller N, Lozano E, Burkett PR, Patel B, Xiao S, Zhu C, Xia J, Tan TG, Sefik E, Yajnik V, Sharpe AH, Quintana FJ, Mathis D, Benoist C, Hafler DA, Kuchroo VK. Treg Cells Expressing the Coinhibitory Molecule TIGIT Selectively Inhibit Proinflammatory Th1 and Th17 Cell Responses. Immunity 2014, 40: 569-581. PMID: 24745333, PMCID: PMC4070748, DOI: 10.1016/j.immuni.2014.02.012.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell ProliferationCells, CulturedCytokinesEosinophilsFibrinogenForkhead Transcription FactorsGene Expression ProfilingGene Expression RegulationImmunosuppression TherapyLymphocyte ActivationMiceMice, Inbred C57BLMice, KnockoutMice, TransgenicReceptors, ImmunologicRespiratory HypersensitivityTh1-Th2 BalanceT-Lymphocyte SubsetsT-Lymphocytes, RegulatoryConceptsTreg cell subsetsTh2 cell responsesTreg cellsCell subsetsCell responsesProinflammatory T helper 1T effector cell proliferationTreg cell-mediated suppressionFibrinogen-like protein 2Allergic airway inflammationT regulatory (Treg) cellsTh2 cytokine productionSuppression of Th1T helper 1Effector cell proliferationTreg signature genesProinflammatory Th1TIGIT expressionAirway inflammationTh17 cellsRegulatory cellsHelper 1Cytokine productionT cellsImmune response
2011
Naturally transmitted segmented filamentous bacteria segregate with diabetes protection in nonobese diabetic mice
Kriegel MA, Sefik E, Hill JA, Wu HJ, Benoist C, Mathis D. Naturally transmitted segmented filamentous bacteria segregate with diabetes protection in nonobese diabetic mice. Proceedings Of The National Academy Of Sciences Of The United States Of America 2011, 108: 11548-11553. PMID: 21709219, PMCID: PMC3136249, DOI: 10.1073/pnas.1108924108.Peer-Reviewed Original ResearchConceptsDiabetes protectionSFB colonizationSmall intestinal lamina propriaSystemic lymphoid tissuesExperimental autoimmune encephalomyelitisNonobese diabetic (NOD) miceT cell compartmentImmune system alterationsType 1 diabetesDifferent Th subsetsSegmented filamentous bacteriaHost physiological functionsNOD miceAutoimmune encephalomyelitisInflammatory arthritisTh17 cellsTh subsetsAutoimmune responseDiabetic miceLymphoid tissueSI-LPSpontaneous modelT cellsLamina propriaMouse model
2010
Differential effects of STAT5 and PI3K/AKT signaling on effector and memory CD8 T-cell survival
Hand TW, Cui W, Jung YW, Sefik E, Joshi NS, Chandele A, Liu Y, Kaech SM. Differential effects of STAT5 and PI3K/AKT signaling on effector and memory CD8 T-cell survival. Proceedings Of The National Academy Of Sciences Of The United States Of America 2010, 107: 16601-16606. PMID: 20823247, PMCID: PMC2944719, DOI: 10.1073/pnas.1003457107.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCD8-Positive T-LymphocytesCell SurvivalDown-RegulationImmunologic MemoryInterleukin-15Lectins, C-TypeLymphocytic choriomeningitis virusMiceMice, Inbred C57BLMice, Mutant StrainsMice, TransgenicPhosphatidylinositol 3-KinasesProto-Oncogene Proteins c-aktReceptors, CytokineReceptors, ImmunologicSignal TransductionSTAT5 Transcription FactorConceptsCD8 T cell survivalT cell survivalPI3K/AktIL-15IL-7IL-15 receptor expressionAntiviral CD8 T cellsBCL2 expressionCD8 T cellsMemory precursor cellsProtective memory cellsAkt activationJAK/STAT5Effector cell deathEffector cellsHomeostatic proliferationReceptor expressionT cellsConstitutive Akt activationCell growth pathwaysConstitutive STAT5 activationViral infectionSTAT5 phosphorylationPrecursor cellsSurvival