Featured Publications
Human PI3Kγ deficiency and its microbiota-dependent mouse model reveal immunodeficiency and tissue immunopathology
Takeda AJ, Maher TJ, Zhang Y, Lanahan SM, Bucklin ML, Compton SR, Tyler PM, Comrie WA, Matsuda M, Olivier KN, Pittaluga S, McElwee JJ, Long Priel DA, Kuhns DB, Williams RL, Mustillo PJ, Wymann MP, Koneti Rao V, Lucas CL. Human PI3Kγ deficiency and its microbiota-dependent mouse model reveal immunodeficiency and tissue immunopathology. Nature Communications 2019, 10: 4364. PMID: 31554793, PMCID: PMC6761123, DOI: 10.1038/s41467-019-12311-5.Peer-Reviewed Original ResearchConceptsT cellsAppropriate adaptive immune responsePet store miceRegulatory T cellsCD4 T cellsAnti-inflammatory functionsAdaptive immune responsesLymphocytic pneumonitisPI3Kγ deficiencyTissue immunopathologyIL-23Memory CD8IL-12TLR stimulationImmune modulationImmune responseGSK3α/βMouse modelMemory BHuman patientsMiceDependent mannerP110γ catalytic subunitFunction mutationsDrug targetsHeterozygous splice mutation in PIK3R1 causes human immunodeficiency with lymphoproliferation due to dominant activation of PI3K
Lucas CL, Zhang Y, Venida A, Wang Y, Hughes J, McElwee J, Butrick M, Matthews H, Price S, Biancalana M, Wang X, Richards M, Pozos T, Barlan I, Ozen A, Rao VK, Su HC, Lenardo MJ. Heterozygous splice mutation in PIK3R1 causes human immunodeficiency with lymphoproliferation due to dominant activation of PI3K. Journal Of Experimental Medicine 2014, 211: 2537-2547. PMID: 25488983, PMCID: PMC4267241, DOI: 10.1084/jem.20141759.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAdultAlternative SplicingAntibody FormationBase SequenceCatalytic DomainCD8-Positive T-LymphocytesCell DifferentiationChild, PreschoolClass Ia Phosphatidylinositol 3-KinaseEnzyme ActivationExonsFemaleGenes, DominantHeterozygoteHumansImmunologic Deficiency SyndromesLymphoproliferative DisordersMaleMolecular Sequence DataMutationPedigreePhosphatidylinositol 3-KinasesProtein Structure, TertiarySequence DeletionSignal TransductionTelomereTOR Serine-Threonine KinasesConceptsT cellsPI3KPI3K subunitsSenescent T cellsRecurrent sinopulmonary infectionsHeterozygous splice site mutationSplice site mutationEffector cellsPeripheral bloodSinopulmonary infectionsHuman immunodeficiencyHeterozygous splice mutationsImmunodeficiency diseaseHealthy subjectsUnique disorderHeterozygous mutationsClass IaPatient cellsProminent expansionK subunitLymphoproliferationPatientsSimilar diseasesShort telomeresDisease
2023
Variable CD18 expression in a 22‐year‐old female with leukocyte adhesion deficiency I: Clinical case and literature review
Bondarenko A, Boyarchuk O, Sakovich I, Polyakova E, Migas A, Kupchinskaya A, Opalinska A, Reich A, Volianska L, Hilfanova A, Lapiy F, Chernyshova L, Volokha A, Zabara D, Belevtsev M, Shman T, Kukharenko L, Goltsev M, Dubouskaya T, Hancharou A, Ji W, Lakhani S, Lucas C, Aleinikova O, Sharapova S. Variable CD18 expression in a 22‐year‐old female with leukocyte adhesion deficiency I: Clinical case and literature review. Clinical Case Reports 2023, 11: e7791. PMID: 37601427, PMCID: PMC10432584, DOI: 10.1002/ccr3.7791.Peer-Reviewed Original ResearchCD18 expressionLAD-1Effector cytotoxic T cellsPyoderma gangrenosum-like lesionsHematopoietic stem cell transplantationGangrenosum-like lesionsRespiratory tract infectionsStem cell transplantationInflammatory skin diseaseCytotoxic T cellsImmune system imbalanceType 1 deficiencyYears of ageLeukocyte adhesion deficiency (LAD) IWhole-exome sequencingAutosomal recessive disorderAutoinflammatory complicationsInfectious manifestationsTract infectionsCell transplantationRare conditionT cellsOral cavitySkin diseasesClinical cases
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 variants
2021
Infections in activated PI3K delta syndrome (APDS)
Brodsky NN, Lucas CL. Infections in activated PI3K delta syndrome (APDS). Current Opinion In Immunology 2021, 72: 146-157. PMID: 34052541, DOI: 10.1016/j.coi.2021.04.010.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsPI3K delta syndromeHematopoietic stem cell transplantAnti-microbial prophylaxisPI3K-delta syndromeStem cell transplantSenescent T cellsSpectrum of infectionsAdaptive immune functionAutosomal dominant disorderCell transplantImmune defectsImmunoglobulin replacementRecurrent infectionsImmunomodulatory agentsTherapy optionsT cellsImmune functionInfection susceptibilityInborn errorsDominant disorderInfectionLymphadenopathyPatientsFunction mutationsImmunodeficiency
2018
Epstein–Barr Virus Susceptibility in Activated PI3Kδ Syndrome (APDS) Immunodeficiency
Carpier JM, Lucas CL. Epstein–Barr Virus Susceptibility in Activated PI3Kδ Syndrome (APDS) Immunodeficiency. Frontiers In Immunology 2018, 8: 2005. PMID: 29387064, PMCID: PMC5776011, DOI: 10.3389/fimmu.2017.02005.Peer-Reviewed Original ResearchPrimary immunodeficiency diseasesAPDS patientsEpstein-Barr virus infectionDefective immunoglobulin productionCell-mediated cytotoxicityRecurrent sinopulmonary infectionsFunction mutationsEBV susceptibilityPI3Kδ syndromeEBV infectionPID patientsLymphoproliferative diseaseSinopulmonary infectionsImmunoglobulin productionB lymphocyte developmentImmune disordersImmunodeficiency diseaseT cellsVirus infectionPatientsLymphocyte biologySenescence markersAntigen receptorGain of functionInfection
2017
Effective “activated PI3Kδ syndrome”–targeted therapy with the PI3Kδ inhibitor leniolisib
Rao VK, Webster S, Dalm VASH, Šedivá A, van Hagen PM, Holland S, Rosenzweig SD, Christ AD, Sloth B, Cabanski M, Joshi AD, de Buck S, Doucet J, Guerini D, Kalis C, Pylvaenaeinen I, Soldermann N, Kashyap A, Uzel G, Lenardo MJ, Patel DD, Lucas CL, Burkhart C. Effective “activated PI3Kδ syndrome”–targeted therapy with the PI3Kδ inhibitor leniolisib. Blood 2017, 130: 2307-2316. PMID: 28972011, PMCID: PMC5701526, DOI: 10.1182/blood-2017-08-801191.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsChemokinesChildChild, PreschoolClass I Phosphatidylinositol 3-KinasesDemographyDose-Response Relationship, DrugFemaleHumansImmunoglobulin MImmunologic Deficiency SyndromesInfantLymph NodesLymphocyte ActivationMaleMolecular Targeted TherapyMutationOrgan SizePhenotypePrimary Immunodeficiency DiseasesProtein Kinase InhibitorsPyridinesPyrimidinesRatsSpleenT-LymphocytesTOR Serine-Threonine KinasesTransfectionConceptsImmune dysregulationT cellsB cellsElevated serum immunoglobulin MPI3K/Akt pathway activityDose-escalation studyLymph node sizeSenescent T cellsWeeks of treatmentDose-dependent suppressionTransitional B cellsTumor necrosis factorDose-dependent reductionPrecision medicine therapiesSerum immunoglobulin MNaive B cellsT cell blastsAkt pathway activityAPDS patientsPI3Kδ pathwayInflammatory markersPD-1Clinical parametersSpleen volumeImmune deficiency
2016
PI3Kδ and primary immunodeficiencies
Lucas CL, Chandra A, Nejentsev S, Condliffe AM, Okkenhaug K. PI3Kδ and primary immunodeficiencies. Nature Reviews Immunology 2016, 16: 702-714. PMID: 27616589, PMCID: PMC5291318, DOI: 10.1038/nri.2016.93.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell DifferentiationCellular SenescenceEnzyme ActivationGene Expression RegulationHumansImmune SystemImmunityImmunologic Deficiency SyndromesLymphocyte ActivationLymphocytesMolecular Targeted TherapyMutationPhosphatidylinositol 3-KinasesPhosphoinositide-3 Kinase InhibitorsProtein SubunitsSignal TransductionConceptsPrimary immunodeficiencyT cellsHeterozygous mutationsAntibody replacement therapyStructural lung damageRegulatory T cellsT cell senescencePI3Kδ inhibitor idelalisibRecurrent sinopulmonary infectionsB-cell malignanciesHerpes family virusesMTOR inhibitor rapamycinPI3Kδ syndromeMost patientsLung damageLymphoma trialsReplacement therapyLymphoproliferative diseaseSinopulmonary infectionsAntibody responseP110δ catalytic subunitCell malignanciesB cellsImmune systemPatients
2013
Molecular Basis of Cell Death Programs in Mature T Cell Homeostasis
Lucas C, Lenardo M. Molecular Basis of Cell Death Programs in Mature T Cell Homeostasis. 2013, 41-59. DOI: 10.1007/978-1-4614-9302-0_3.Peer-Reviewed Original ResearchPathological immune reactionsNumber of lymphocytesT cell nicheT cell homeostasisWhite blood cellsT cell apoptosisGraft rejectionAutoimmune disordersImmune cellsImmunological memoryLong-term protectionT cellsT lymphocytesImmune reactionsAntigen specificityInfectious agentsLymphocytesBlood cellsCell apoptosisMolecular pathwaysCell death mechanismsMature T cell homeostasisCell homeostasisCell deathDeath mechanismsMg2+ Regulates Cytotoxic Functions of NK and CD8 T Cells in Chronic EBV Infection Through NKG2D
Chaigne-Delalande B, Li FY, O’Connor G, Lukacs MJ, Jiang P, Zheng L, Shatzer A, Biancalana M, Pittaluga S, Matthews HF, Jancel TJ, Bleesing JJ, Marsh RA, Kuijpers TW, Nichols KE, Lucas CL, Nagpal S, Mehmet H, Su HC, Cohen JI, Uzel G, Lenardo MJ. Mg2+ Regulates Cytotoxic Functions of NK and CD8 T Cells in Chronic EBV Infection Through NKG2D. Science 2013, 341: 186-191. PMID: 23846901, PMCID: PMC3894782, DOI: 10.1126/science.1240094.Peer-Reviewed Original ResearchConceptsEpstein-Barr virusNatural killerMagnesium transporter 1T cellsChronic EBV infectionCD8 T cellsIntracellular free magnesium concentrationEBV infectionCytolytic responsesCytotoxic functionReceptor NKG2DMagnesium supplementationBasal intracellularAntiviral immunityCytolytic activityFree magnesium concentrationNKG2DTransporter 1Genetic deficiencyDefective expressionCritical regulatorMagnesium concentrationKillerCellsIntracellular
2011
LAG-3, TGF-β, and cell-intrinsic PD-1 inhibitory pathways contribute to CD8 but not CD4 T-cell tolerance induced by allogeneic BMT with anti-CD40L
Lucas CL, Workman CJ, Beyaz S, LoCascio S, Zhao G, Vignali DA, Sykes M. LAG-3, TGF-β, and cell-intrinsic PD-1 inhibitory pathways contribute to CD8 but not CD4 T-cell tolerance induced by allogeneic BMT with anti-CD40L. Blood 2011, 117: 5532-5540. PMID: 21422469, PMCID: PMC3109721, DOI: 10.1182/blood-2010-11-318675.Peer-Reviewed Original ResearchMeSH KeywordsAdoptive TransferAnimalsAntigens, CDAntigens, SurfaceApoptosis Regulatory ProteinsB7-1 AntigenB7-H1 AntigenBone Marrow TransplantationCD40 LigandCD4-Positive T-LymphocytesCD8-Positive T-LymphocytesCTLA-4 AntigenFemaleImmune ToleranceLymphocyte Activation Gene 3 ProteinMembrane GlycoproteinsMiceMice, Inbred C57BLMice, KnockoutMice, TransgenicModels, ImmunologicalPeptidesProgrammed Cell Death 1 Ligand 2 ProteinProgrammed Cell Death 1 ReceptorSignal TransductionTransforming Growth Factor betaTransplantation, HomologousConceptsT cell toleranceCD4 T cell tolerancePeripheral CD8PD-1LAG-3T cellsCD8 T cell tolerance inductionPD-1/PD-L1 pathwayCD8 T cell tolerancePD-1 inhibitory pathwayT cell tolerance inductionAdoptive transfer studiesAllogeneic BM transplantationPD-L1 pathwayAlloreactive T cellsMixed hematopoietic chimerismT cell-intrinsic requirementB7.1/B7.2Cell-intrinsic requirementTGF-β signalingAllogeneic BMTPD-L1Mixed chimerasPD-L2Tolerance induction
2009
A CD8 T cell–intrinsic role for the calcineurin-NFAT pathway for tolerance induction in vivo
Fehr T, Lucas CL, Kurtz J, Onoe T, Zhao G, Hogan T, Vallot C, Rao A, Sykes M. A CD8 T cell–intrinsic role for the calcineurin-NFAT pathway for tolerance induction in vivo. Blood 2009, 115: 1280-1287. PMID: 20007805, PMCID: PMC2826238, DOI: 10.1182/blood-2009-07-230680.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntibodies, MonoclonalApoptosis Regulatory ProteinsBone Marrow TransplantationCalcineurinCD40 LigandCD4-Positive T-LymphocytesCD8-Positive T-LymphocytesCyclosporineFemaleFlow CytometryGraft SurvivalImmune ToleranceMiceMice, Inbred C57BLMice, TransgenicNFATC Transcription FactorsReceptors, Antigen, T-CellSignal TransductionThymectomyTransplantation ChimeraConceptsCD8 T cellsCalcineurin/NFAT pathwayTolerance inductionCD8 toleranceT cell receptorCD4 cellsT cellsAllogeneic bone marrow transplantation modelNFAT pathwayT cell-intrinsic roleAnti-CD154 antibodyFailure of CD8Adoptive transfer studiesBone marrow transplantation modelBone marrow transplantationCell-intrinsic roleCalcineurin-NFAT pathwayCD8 cellsRegulatory cellsTransplantation toleranceMarrow transplantationTransplantation modelAnergy inductionNFAT1 deficiencyNuclear factorCD40L-specific mAb mediates its tolerogenic effects through engagement of FcgRIIB, not via depletion of activated T cells (141.17)
Lucas C, Fehr T, Haspot F, Sykes M. CD40L-specific mAb mediates its tolerogenic effects through engagement of FcgRIIB, not via depletion of activated T cells (141.17). The Journal Of Immunology 2009, 182: 141.17-141.17. DOI: 10.4049/jimmunol.182.supp.141.17.Peer-Reviewed Original ResearchCD8 T cellsBone marrow cellsAllogeneic bone marrow cellsT cellsCD8 cellsCD8 T cell toleranceLong-term mixed chimerismPeripheral CD8 T cellsTotal body irradiationDepletion of activated T cellsRecipient B cellsT cell toleranceFc-dependent functionsCD40L mAbDonor BMMixed chimerismDonor leukocytesBody irradiationKO recipientsB6 miceTolerogenic effectGraft acceptanceMarrow cellsFcgRIIbCD8