2024
Circulating tumor-reactive KIR+CD8+ T cells suppress anti-tumor immunity in patients with melanoma
Lu B, Lucca L, Lewis W, Wang J, Nogueira C, Heer S, Rayon-Estrada V, Axisa P, Reeves S, Buitrago-Pocasangre N, Pham G, Kojima M, Wei W, Aizenbud L, Bacchiocchi A, Zhang L, Walewski J, Chiang V, Olino K, Clune J, Halaban R, Kluger Y, Coyle A, Kisielow J, Obermair F, Kluger H, Hafler D. Circulating tumor-reactive KIR+CD8+ T cells suppress anti-tumor immunity in patients with melanoma. Nature Immunology 2024, 1-10. PMID: 39609626, DOI: 10.1038/s41590-024-02023-4.Peer-Reviewed Original ResearchCD8+ T cellsAnti-tumor immunityRegulatory T cellsT cellsSubpopulation of CD8+ T cellsCytotoxic CD8+ T cellsHuman CD8+ T cellsTumor antigen-specific CD8Impaired anti-tumor immunityTumor antigen-specificPoor overall survivalTumor rejectionKIR expressionOverall survivalTumor antigensImmune evasionCellular mediatorsHuman cancersCD8MelanomaTumorTranscriptional programsFunctional heterogeneityImmunityPatientsCholesterol promotes IFNG mRNA expression in CD4+ effector/memory cells by SGK1 activation
Hanin A, Comi M, Sumida T, Hafler D. Cholesterol promotes IFNG mRNA expression in CD4+ effector/memory cells by SGK1 activation. Life Science Alliance 2024, 7: e202402890. PMID: 39366761, PMCID: PMC11452476, DOI: 10.26508/lsa.202402890.Peer-Reviewed Original ResearchConceptsCentral nervous systemT cellsEffector/memory cellsCentral nervous system milieuT cell environmentCD4 T cellsIFNG mRNA expressionCXCR3<sup>+</sup> cellsT cell homeostasisInhibition of SGK1Targeting lipid pathwaysMaintenance of immune surveillanceSerum/glucocorticoid-regulated kinaseImmune surveillanceHealthy donorsCytotoxic capacityEffector responsesInflammatory conditionsSGK1 activityMRNA expressionNervous systemSGK1Metabolic conditionsLipid pathwaysTissue adaptationAn autoimmune transcriptional circuit drives FOXP3+ regulatory T cell dysfunction
Sumida T, Lincoln M, He L, Park Y, Ota M, Oguchi A, Son R, Yi A, Stillwell H, Leissa G, Fujio K, Murakawa Y, Kulminski A, Epstein C, Bernstein B, Kellis M, Hafler D. An autoimmune transcriptional circuit drives FOXP3+ regulatory T cell dysfunction. Science Translational Medicine 2024, 16: eadp1720. PMID: 39196959, DOI: 10.1126/scitranslmed.adp1720.Peer-Reviewed Original ResearchConceptsForkhead box P3Autoimmune diseasesCD4<sup>+</sup>Foxp3<sup>+</sup> regulatory T cellsMultiple sclerosisFoxp3<sup>+</sup> regulatory T cellsRegulatory T cell dysfunctionPR domain zinc finger protein 1Zinc finger protein 1Glucocorticoid-regulated kinase 1Regulatory T cellsT cell dysfunctionDisorder of young adultsAutoimmune disease multiple sclerosisDisease multiple sclerosisExpression of serumTranscriptional circuitsEpigenomic profilingShort isoformPrevent autoimmunityUpstream regulatorT cellsHuman autoimmunityEvolutionary emergenceKinase 1Molecular mechanismsThe regulation and differentiation of regulatory T cells and their dysfunction in autoimmune diseases
Sumida T, Cheru N, Hafler D. The regulation and differentiation of regulatory T cells and their dysfunction in autoimmune diseases. Nature Reviews Immunology 2024, 24: 503-517. PMID: 38374298, PMCID: PMC11216899, DOI: 10.1038/s41577-024-00994-x.Peer-Reviewed Original ResearchTreg cell dysfunctionTreg cellsAutoimmune diseasesCell dysfunctionSuppressive function of Treg cellsDifferentiation of regulatory T cellsFunction of Treg cellsDiscovery of Foxp3Foxp3-independent mechanismsTreg cell suppressionRegulatory T cellsTreg cell functionTranscription factor Foxp3Systemic lupus erythematosusRegulate immune responsesInflammatory bowel diseaseFOXP3 mutationsFoxp3-dependentSystemic autoinflammationRegulatory TIPEX syndromeCell lineage determinationT cellsTregsLupus erythematosus
2023
Prior cycles of anti-CD20 antibodies affect antibody responses after repeated SARS-CoV-2 mRNA vaccination
Asashima H, Kim D, Wang K, Lele N, Buitrago-Pocasangre N, Lutz R, Cruz I, Raddassi K, Ruff W, Racke M, Wilson J, Givens T, Grifoni A, Weiskopf D, Sette A, Kleinstein S, Montgomery R, Shaw A, Li F, Fan R, Hafler D, Tomayko M, Longbrake E. Prior cycles of anti-CD20 antibodies affect antibody responses after repeated SARS-CoV-2 mRNA vaccination. JCI Insight 2023, 8: e168102. PMID: 37606046, PMCID: PMC10543713, DOI: 10.1172/jci.insight.168102.Peer-Reviewed Original ResearchConceptsSARS-CoV-2 mRNA vaccinationB-cell-depleted patientsB-cell depletionAntibody responseMRNA vaccinationThird doseCell depletionT cellsClaude D. Pepper Older Americans Independence CenterB cellsNational Multiple Sclerosis SocietyAnti-CD20 antibodySpike-specific antibodiesMultiple Sclerosis SocietyLow cumulative exposureLogistic regression modelsImportant clinical needCD20 therapyCD20 treatmentMost patientsThird vaccineSerologic responseVaccine dosesMRNA vaccinesVaccination strategiesBSBM-18 SINGLE-CELL PROFILING TUMOR-INFILTRATING IMMUNE CELLS REVEALS CXCL13+ FOLLICULAR HELPER-LIKE CD4+ T CELLS IN HUMAN BRAIN TUMORS
Lu B, Lucca L, DiStasio M, Liu Y, Pham G, Buitrago-Pocasangre N, Arnal-Estape A, Moliterno J, Chiang V, Omuro A, Hafler D. BSBM-18 SINGLE-CELL PROFILING TUMOR-INFILTRATING IMMUNE CELLS REVEALS CXCL13+ FOLLICULAR HELPER-LIKE CD4+ T CELLS IN HUMAN BRAIN TUMORS. Neuro-Oncology Advances 2023, 5: iii4-iii4. PMCID: PMC10402449, DOI: 10.1093/noajnl/vdad070.014.Peer-Reviewed Original ResearchT cell populationsT cell functionT cellsHigh-grade gliomasBrain metastasesHuman brain tumorsImmune cellsBrain tumorsNon-small cell lung cancer brain metastasesB cellsAnti-PD-1 therapy responseCell lung cancer brain metastasesLung cancer brain metastasesProductive antitumor immune responsesFollicular helper T cellsT-cell receptor sequencingTumor-infiltrating T cellsAntitumor T-cell functionCancer brain metastasesCo-inhibitory receptorsAntitumor immune responseCell receptor sequencingLonger overall survivalCell functionTertiary lymphoid structuresRegulatory T cells in peripheral tissue tolerance and diseases
Cheru N, Hafler D, Sumida T. Regulatory T cells in peripheral tissue tolerance and diseases. Frontiers In Immunology 2023, 14: 1154575. PMID: 37197653, PMCID: PMC10183596, DOI: 10.3389/fimmu.2023.1154575.Peer-Reviewed Original ResearchConceptsTissue-resident TregsRegulatory T cellsT cellsResident TregsTissue TregsAutoimmune diseasesCommon human autoimmune diseasesAutoreactive T cellsHuman autoimmune diseasesNon-immune cellsNon-lymphoid tissuesTissue-resident cellsTreg poolTreg studiesEffector cytokinesPeripheral toleranceTreg functionIPEX syndromeImmune homeostasisSpecific tissue environmentsTregsSuppressive functionLoss of functionResident cellsGene signatureDifferential effects of anti-CD20 therapy on CD4 and CD8 T cells and implication of CD20-expressing CD8 T cells in MS disease activity
Shinoda K, Li R, Rezk A, Mexhitaj I, Patterson K, Kakara M, Zuroff L, Bennett J, von Büdingen H, Carruthers R, Edwards K, Fallis R, Giacomini P, Greenberg B, Hafler D, Ionete C, Kaunzner U, Lock C, Longbrake E, Pardo G, Piehl F, Weber M, Ziemssen T, Jacobs D, Gelfand J, Cross A, Cameron B, Musch B, Winger R, Jia X, Harp C, Herman A, Bar-Or A. Differential effects of anti-CD20 therapy on CD4 and CD8 T cells and implication of CD20-expressing CD8 T cells in MS disease activity. Proceedings Of The National Academy Of Sciences Of The United States Of America 2023, 120: e2207291120. PMID: 36634138, PMCID: PMC9934304, DOI: 10.1073/pnas.2207291120.Peer-Reviewed Original ResearchConceptsEarly disease activityDisease activityCD8 T cellsT cellsCD20 therapyPeripheral blood mononuclear cellsCellular immune profilesNew disease activityMS disease activityT cell poolMultiple sclerosis patientsAnti-inflammatory profileBlood mononuclear cellsTreatment-associated changesMultiparametric flow cytometryCentral nervous systemFurther dosingRepeat infusionsImmune profileMS patientsSclerosis patientsValidation cohortMononuclear cellsRelapse developmentImmune cascade
2022
A multiple sclerosis–protective coding variant reveals an essential role for HDAC7 in regulatory T cells
Axisa P, Yoshida T, Lucca L, Kasler H, Lincoln M, Pham G, Del Priore D, Carpier J, Lucas C, Verdin E, Sumida T, Hafler D. A multiple sclerosis–protective coding variant reveals an essential role for HDAC7 in regulatory T cells. Science Translational Medicine 2022, 14: eabl3651. PMID: 36516268, DOI: 10.1126/scitranslmed.abl3651.Peer-Reviewed Original ResearchConceptsExperimental autoimmune encephalitisRegulatory T cellsHistone deacetylase 7Multiple sclerosisT cellsMouse modelFunction of Foxp3CD4 T cellsHigher suppressive capacityVivo modelingAutoimmune encephalitisEAE severityImmunosuppressive subsetAutoimmune diseasesImmunomodulatory roleSuppressive capacityImmune cellsDisease onsetDistinct molecular classesSusceptibility lociGenetic susceptibility lociSingle-cell RNA sequencingDisease riskPatient samplesProtective variantsImpaired TIGIT expression on B cells drives circulating follicular helper T cell expansion in multiple sclerosis
Asashima H, Axisa PP, Pham THG, Longbrake EE, Ruff WE, Lele N, Cohen I, Raddassi K, Sumida TS, Hafler DA. Impaired TIGIT expression on B cells drives circulating follicular helper T cell expansion in multiple sclerosis. Journal Of Clinical Investigation 2022, 132: e156254. PMID: 36250467, PMCID: PMC9566906, DOI: 10.1172/jci156254.Peer-Reviewed Original ResearchConceptsRelapsing-remitting multiple sclerosisMemory B cellsCTfh cellsB cellsTIGIT expressionMultiple sclerosisT cellsFollicular helper T cellsHealthy age-matched controlsB-cell depletionT cell expansionHelper T cellsAge-matched controlsB cell functionB-cell pathwayDifferential gene expression signaturesTfh cellsDisease activityGene expression signaturesCell depletionCD40 ligandTranscription factor TCF4Disease pathogenesisImmune systemNew MRIBasic principles of neuroimmunology
Yoshida TM, Wang A, Hafler DA. Basic principles of neuroimmunology. Seminars In Immunopathology 2022, 44: 685-695. PMID: 35732977, DOI: 10.1007/s00281-022-00951-7.Peer-Reviewed Original ResearchConceptsNeuro-immune interactionsCentral nervous systemImmune privilegeCerebrospinal fluidCNS-resident immune cellsImmune-derived cytokinesResident T cellsImmune cell infiltrationImmune-privileged organMeningeal lymphatic systemIntroduction of antigenImmune compartmentNeuroinflammatory diseasesNeurological functionCNS homeostasisCell infiltrationHarmful inflammationImmune cellsPeripheral organsT cellsImmune responseLeukocyte traffickingNervous systemImmune systemLymphatic systemFatty Acid Metabolism and T Cells in Multiple Sclerosis
Pompura SL, Hafler DA, Dominguez-Villar M. Fatty Acid Metabolism and T Cells in Multiple Sclerosis. Frontiers In Immunology 2022, 13: 869197. PMID: 35603182, PMCID: PMC9116144, DOI: 10.3389/fimmu.2022.869197.Peer-Reviewed Original ResearchConceptsT cell functionT cellsMultiple sclerosisSpecific lipid speciesEffector T cellsRegulatory T cellsCell functionT helper subsetsMetabolic programsT cell activationT cell transitionLipid speciesFatty acid metabolismTh subsetsHelper subsetsEffector stateBody of evidenceCell activationDisease settingsDisease statesFunctional phenotypeOrganismal levelAcid metabolismMetabolic remodelingNutrient availabilityType I interferon transcriptional network regulates expression of coinhibitory receptors in human T cells
Sumida TS, Dulberg S, Schupp JC, Lincoln MR, Stillwell HA, Axisa PP, Comi M, Unterman A, Kaminski N, Madi A, Kuchroo VK, Hafler DA. Type I interferon transcriptional network regulates expression of coinhibitory receptors in human T cells. Nature Immunology 2022, 23: 632-642. PMID: 35301508, PMCID: PMC8989655, DOI: 10.1038/s41590-022-01152-y.Peer-Reviewed Original ResearchConceptsCoinhibitory receptor expressionHuman T cellsIFN-I responsesCoinhibitory receptorsT cellsTIGIT expressionReceptor expressionAcute SARS-CoV-2 infectionPD-1/TimSARS-CoV-2 infectionEnhancement of immunotherapyType 1 interferonT-cell featuresLAG-3Infectious diseasesDifferent temporal kineticsTranscription factorsCancer therapyReceptorsCell featuresKey transcription factorIFNPresent studyMRNA profilingKey regulatorTCR-sequencing in cancer and autoimmunity: barcodes and beyond
Pauken KE, Lagattuta KA, Lu BY, Lucca LE, Daud AI, Hafler DA, Kluger HM, Raychaudhuri S, Sharpe AH. TCR-sequencing in cancer and autoimmunity: barcodes and beyond. Trends In Immunology 2022, 43: 180-194. PMID: 35090787, PMCID: PMC8882139, DOI: 10.1016/j.it.2022.01.002.Peer-Reviewed Original ResearchConceptsT cell receptorT cellsMolecular barcodesProgrammed Death-1 BlockadeTCR sequencesDeath-1 blockadeUnique TCR sequencesNaïve T cellsT cell functionCell divisionMolecular phenotypesBarcodesImmune responseAntigen specificitySingle cellsCell receptorCell functionRecent technological advancesCancerTCR dataCellsSingle-cell multi-omics reveals dyssynchrony of the innate and adaptive immune system in progressive COVID-19
Unterman A, Sumida TS, Nouri N, Yan X, Zhao AY, Gasque V, Schupp JC, Asashima H, Liu Y, Cosme C, Deng W, Chen M, Raredon MSB, Hoehn KB, Wang G, Wang Z, DeIuliis G, Ravindra NG, Li N, Castaldi C, Wong P, Fournier J, Bermejo S, Sharma L, Casanovas-Massana A, Vogels CBF, Wyllie AL, Grubaugh ND, Melillo A, Meng H, Stein Y, Minasyan M, Mohanty S, Ruff WE, Cohen I, Raddassi K, Niklason L, Ko A, Montgomery R, Farhadian S, Iwasaki A, Shaw A, van Dijk D, Zhao H, Kleinstein S, Hafler D, Kaminski N, Dela Cruz C. Single-cell multi-omics reveals dyssynchrony of the innate and adaptive immune system in progressive COVID-19. Nature Communications 2022, 13: 440. PMID: 35064122, PMCID: PMC8782894, DOI: 10.1038/s41467-021-27716-4.Peer-Reviewed Original ResearchMeSH KeywordsAdaptive ImmunityAgedAntibodies, Monoclonal, HumanizedCD4-Positive T-LymphocytesCD8-Positive T-LymphocytesCells, CulturedCOVID-19COVID-19 Drug TreatmentFemaleGene Expression ProfilingGene Expression RegulationHumansImmunity, InnateMaleReceptors, Antigen, B-CellReceptors, Antigen, T-CellRNA-SeqSARS-CoV-2Single-Cell AnalysisConceptsProgressive COVID-19B cell clonesSingle-cell analysisT cellsImmune responseMulti-omics single-cell analysisCOVID-19Cell clonesAdaptive immune interactionsSevere COVID-19Dynamic immune responsesGene expressionSARS-CoV-2 virusAdaptive immune systemSomatic hypermutation frequenciesCellular effectsProtein markersEffector CD8Immune signaturesProgressive diseaseHypermutation frequencyProgressive courseClassical monocytesClonesImmune interactions
2021
Single cell immunophenotyping of the skin lesion erythema migrans Identifies IgM memory B cells
Jiang R, Meng H, Raddassi K, Fleming I, Hoehn KB, Dardick KR, Belperron AA, Montgomery RR, Shalek AK, Hafler DA, Kleinstein SH, Bockenstedt LK. Single cell immunophenotyping of the skin lesion erythema migrans Identifies IgM memory B cells. JCI Insight 2021, 6: e148035. PMID: 34061047, PMCID: PMC8262471, DOI: 10.1172/jci.insight.148035.Peer-Reviewed Original ResearchConceptsMemory B cellsErythema migransB cellsEM lesionsIgM memory B cellsLyme diseaseB-cell receptor sequencingSkin infection siteCell receptor sequencingEarly Lyme diseaseLocal antigen presentationSkin immune responsesB cell populationsSingle-cell immunophenotypingMHC class II genesUninvolved skinImmune cellsSpirochetal infectionAntigen presentationCell immunophenotypingT cellsImmune responseIsotype usageAntibody productionInitial signsCirculating clonally expanded T cells reflect functions of tumor-infiltrating T cells
Lucca LE, Axisa PP, Lu B, Harnett B, Jessel S, Zhang L, Raddassi K, Zhang L, Olino K, Clune J, Singer M, Kluger HM, Hafler DA. Circulating clonally expanded T cells reflect functions of tumor-infiltrating T cells. Journal Of Experimental Medicine 2021, 218: e20200921. PMID: 33651881, PMCID: PMC7933991, DOI: 10.1084/jem.20200921.Peer-Reviewed Original ResearchConceptsTumor-infiltrating T cellsT cellsUnique transcriptional patternsFeatures of exhaustionLongitudinal immune monitoringPeripheral immune environmentsT cell responsesT cell functionSingle-cell levelTranscriptional patternsTCR sharingTerminal exhaustionImmune environmentImmune monitoringCancer immunotherapyMetastatic melanomaEffector functionsCell responsesTumor tissueGene signatureTumorsCell functionImmunotherapyTCRαβBloodOleic acid restores suppressive defects in tissue-resident FOXP3 regulatory T cells from patients with multiple sclerosis
Pompura SL, Wagner A, Kitz A, Laperche J, Yosef N, Dominguez-Villar M, Hafler D. Oleic acid restores suppressive defects in tissue-resident FOXP3 regulatory T cells from patients with multiple sclerosis. Journal Of Clinical Investigation 2021, 131 PMID: 33170805, PMCID: PMC7810477, DOI: 10.1172/jci138519.Peer-Reviewed Original ResearchConceptsMultiple sclerosisAdipose tissueFoxp3 regulatory T cellsExpression of Foxp3Regulatory T cellsTreg suppressive functionProinflammatory arachidonic acidHuman adipose tissuePhosphorylation of STAT5Treg homeostasisFatty acidsPeripheral bloodTissue residencyHealthy donorsInflammatory signalsT cellsTregsFree fatty acidsSuppressive functionArachidonic acidPatientsOleic acidOxidative phosphorylationTranscriptomic programsFoxp3
2020
Transcriptomic and clonal characterization of T cells in the human central nervous system
Pappalardo JL, Zhang L, Pecsok MK, Perlman K, Zografou C, Raddassi K, Abulaban A, Krishnaswamy S, Antel J, van Dijk D, Hafler DA. Transcriptomic and clonal characterization of T cells in the human central nervous system. Science Immunology 2020, 5 PMID: 32948672, PMCID: PMC8567322, DOI: 10.1126/sciimmunol.abb8786.Peer-Reviewed Original ResearchConceptsCentral nervous systemCSF of patientsT cellsCerebrospinal fluidMultiple sclerosisImmune surveillanceNervous systemCSF T cellsHuman central nervous systemHealthy human donorsT cell activationImmune dysfunctionNeuroinflammatory diseasesCytotoxic capacityHealthy donorsHealthy individualsCell activationHuman donorsTissue adaptationPatientsClonal characterizationExpression of genesCellsSurveillanceFurther characterizationB Cells, T Cells and Inflammatory CSF Biomarkers in Primary Progressive MS and Relapsing MS in the OBOE (Ocrelizumab Biomarker Outcome Evaluation) Trial (1635)
Bar-Or A, Bennett J, Von Budingen H, Carruthers R, Edwards K, Fallis R, Fiore D, Gelfand J, Giacomini P, Greenberg B, Hafler D, Longbrake E, Assman B, Ionete C, Kaunzner U, Lock C, Ma X, Musch B, Pardo G, Pei J, Piehl F, Weber M, Ziemssen T, Herman A, Harp C, Cross A. B Cells, T Cells and Inflammatory CSF Biomarkers in Primary Progressive MS and Relapsing MS in the OBOE (Ocrelizumab Biomarker Outcome Evaluation) Trial (1635). Neurology 2020, 94 DOI: 10.1212/wnl.94.15_supplement.1635.Peer-Reviewed Original Research