Robert Tigelaar, MD
Professor Emeritus of DermatologyCards
Contact Info
Dermatology
PO Box 208059, 333 Cedar Street
New Haven, CT 06520-8059
United States
About
Titles
Professor Emeritus of Dermatology
Appointments
Departments & Organizations
Education & Training
- Resident
- University of Washington (1979)
- Fellow
- National Institutes of Health (1976)
- Resident
- New York University Medical Center (1970)
- MD
- University of Michigan (1968)
Board Certifications
Dermatology
- Certification Organization
- AB of Dermatology
- Original Certification Date
- 1981
Research
Overview
Dr. Robert Tigelaar's major research focus continues to be the dendritic epidermal d T cells (DETC) populating the skin of all normal strains of mice. A number of longstanding collaborations between the Tigelaar lab and those of Michael Girardi (Dermatology) and Adrian Hayday (Guy’s Immunobiology [London]) include:
- The generation and characterization of a Vg5-/- “knockout” mouse selectively deficient in DETCs expressing the TCR prototypically seen on >95% of such cells; studies of such mice unexpectedly showed that in the absence of Vg5, the replacement population of d DETC includes a significant number of cells expressing a Vd1/d1 TCR with a similar 3-D conformation as the conventional Vg5/Vd1 TCR (as defined by an anti-clonotypic antibody to the Vg5/Vd1 TCR)
- Documentation that some (e.g., FVB and NOD), but not other (B6) strains of mice genetically deficient in d T cells (d-/- mice) develop a localized (ears) cutaneous inflammation/ spontaneous dermatitis (SpD) that is dependent (like atopic dermatitis) both upon conventional aß T cells and upon an appropriate external environment.
Adoptive transfer studies showed that Vg5+ DETC but not systemic Vg5- d cells were necessary and sufficient to down-regulate SpD. Finally, crosses of susceptible (NOD) and resistant (C57BL/6) d-/- mice which showed that susceptibility to SpD behaves as a recessive trait, have been recently analyzed by genome-wide, microsatellite mapping; these studies clearly indicate that several distinct genetic intervals contribute to the regulation of this cutaneous inflammatory response. Ongoing studies in this arena:
- To characterize in more detail the pathology in SpD normally down-regulated by skin-associated DETC
- To characterize the genes expressed by “resting” DETC and in vitro “activated” DETC by serial analysis of gene expression (SAGE)
- To investigate the potentials of selected candidate DETC cytokines/effector molecules to down-regulate SpD
Recent studies of a spontaneous mutation arising in a substrain of FVB mice that results in a striking deficiency in the skin of the prototypic Vg5/Vd1+ DETCs seen in other normal mice strains led to further studies that proved that this heritable defect in a dominant gene resided in fetal thymic epithelial cells resulting in a failure of positive selection in the thymus (and subsequent migration to the skin) of the Vg5/Vd1+ fetal thymic precursors. (These results, published in Nature Immunology, present the first definitive proof that d cells resident in epithelial interfaces with the external environment, like conventional recirculating aß T cells, undergo positive selection in the thymus.) In a productive collaborative followup study between Drs. Tigelaar, Girardi and Hayday with Richard Lifton (Genetics) recently published in Nature Genetics, it was shown that this defect is caused by mutation in Skint1, a newly identified gene expressed in thymus and skin that encodes a protein with immunoglobulin-like and transmembrane domains. Skint1 is the prototypic member of a rapidly evolving family of at least 11 genes in mouse, with greatest similarity to the butyrophilin genes. These findings define a new family of proteins mediating key epithelial-immune interactions.
- Characterizing the genes expressed by "resting" and "activated" DETC by serial analysis of gene expression (SAGE) and comparing such expression patterns with other IEL and recirculating T cell subsets.
- Investigating selected candidate DETC anti-inflammatory cytokines/effector molecules by reconstituting TCR delta-/- recipients with DETC precursors rendered deficient (via gene "knockout" or siRNA "knock-down") in candidate anti-inflammatory molecules.
- Utilizing genome-wide microsatellite mapping, to identify the genetic interval(s), and ultimately the specific genes, controlling susceptibility/resistance to the spontaneous dermatitis that develops in some, but not other TCR delta -/- mice.
- Utilizing cellular, molecular and genetic studies to identify the physiologic ligands for TCR gamma/delta+ T cells that trigger both their positive selection in the thymus and their activation in peripheral epithelial tissues such as the skin and GI tract.
Medical Subject Headings (MeSH)
Research at a Glance
Yale Co-Authors
Publications Timeline
Research Interests
Michael Girardi, MD, FAAD
Earl Glusac, MD
Kalman Watsky, MD
Daniel Zelterman, PhD
David J Leffell, MDCM
Jean Bolognia, MD
Skin
Dermatitis, Contact
Lymphoma, T-Cell, Cutaneous
Dermatitis, Atopic
Publications
2011
Response: validity of evidence demonstrating efficacy of extracorporeal photochemotherapy
Berger C, Lewis J, Girardi M, Tigelaar R, Edelson R. Response: validity of evidence demonstrating efficacy of extracorporeal photochemotherapy. Blood 2011, 117: 367. PMID: 21212292, PMCID: PMC3037285, DOI: 10.1182/blood-2010-11-317107.Peer-Reviewed Original Research
2009
Skin immune surveillance by T cells—A new order?
Strid J, Tigelaar RE, Hayday AC. Skin immune surveillance by T cells—A new order? Seminars In Immunology 2009, 21: 110-120. PMID: 19369094, DOI: 10.1016/j.smim.2009.03.002.Peer-Reviewed Original ResearchCitationsMeSH Keywords and ConceptsConceptsImmune surveillanceAdaptive immune surveillanceStress-induced antigensSystemic immune cellsSkin immune surveillanceLocal lymphocytesOrgan dysfunctionDendritic cellsImmune cellsT cellsEpithelial cellsTissue integrityCellsSurveillanceBody surfaceImmunopathologyImmunoregulationDysfunctionLymphocytesInfectionAntigenImmunoprotectionStress response
2008
Skint1, the prototype of a newly identified immunoglobulin superfamily gene cluster, positively selects epidermal γδ T cells
Boyden LM, Lewis JM, Barbee SD, Bas A, Girardi M, Hayday AC, Tigelaar RE, Lifton RP. Skint1, the prototype of a newly identified immunoglobulin superfamily gene cluster, positively selects epidermal γδ T cells. Nature Genetics 2008, 40: 656-662. PMID: 18408721, PMCID: PMC4167720, DOI: 10.1038/ng.108.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsDevelopment of Immunogenic Tumor-Loaded Dendritic Cells Through Physical Perturbation and Apoptotic Cell Loading
Shen X, Berger CL, Tigelaar R, Edelson RL. Development of Immunogenic Tumor-Loaded Dendritic Cells Through Physical Perturbation and Apoptotic Cell Loading. Immunological Investigations 2008, 37: 798-821. PMID: 18991097, DOI: 10.1080/08820130802403358.Peer-Reviewed Original ResearchCitationsMeSH Keywords and ConceptsMeSH KeywordsAntigen PresentationAntigens, CDAntigens, NeoplasmApoptosisB7-1 AntigenCancer VaccinesCD8-Positive T-LymphocytesCell DifferentiationCell Line, TumorCytotoxicity, ImmunologicDendritic CellsHumansImmunoglobulinsLymphocyte ActivationLymphoma, T-CellMechanotransduction, CellularMembrane GlycoproteinsMonocytesPerforinReceptors, CCR7Silicon DioxideConceptsT cellsDendritic cellsAllogeneic T cell proliferationCD8 T cellsLevels of perforinChemokine receptor CCR7T cell proliferationApoptotic tumor cellsUniverse of antigensDC vaccinesImmunogenic tumorsImmature DCsReceptor CCR7TNF-alphaPassage of leukocytesIFN-gammaHuman monocytesMonocytesTumor cellsPotent inductionCell apoptosisPhenotypic conversionCell proliferationApoptotic cellsCells induces
2007
Characterizing tumor-promoting T cells in chemically induced cutaneous carcinogenesis
Roberts SJ, Ng BY, Filler RB, Lewis J, Glusac EJ, Hayday AC, Tigelaar RE, Girardi M. Characterizing tumor-promoting T cells in chemically induced cutaneous carcinogenesis. Proceedings Of The National Academy Of Sciences Of The United States Of America 2007, 104: 6770-6775. PMID: 17412837, PMCID: PMC1871860, DOI: 10.1073/pnas.0604982104.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsT cell deficiencyT cellsCell deficiencyPRO cellsCell-deficient miceTumor-infiltrating lymphocytesAnti-tumor responseT cell populationsInflammation-associated carcinogenesisT cell receptorImmunotherapeutic strategiesRegulatory cellsCancer immunosurveillanceCell reconstitutionEpidemiologic linkCutaneous carcinogenesisTumor incidenceCyclooxygenase-2Activated populationCell receptorNovel populationCell populationsChemical carcinogenesisCarcinogenesisLymphocytes
2005
Sustained localized expression of ligand for the activating NKG2D receptor impairs natural cytotoxicity in vivo and reduces tumor immunosurveillance
Oppenheim DE, Roberts SJ, Clarke SL, Filler R, Lewis JM, Tigelaar RE, Girardi M, Hayday AC. Sustained localized expression of ligand for the activating NKG2D receptor impairs natural cytotoxicity in vivo and reduces tumor immunosurveillance. Nature Immunology 2005, 6: 928-937. PMID: 16116470, DOI: 10.1038/ni1239.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsMeSH Keywords9,10-Dimethyl-1,2-benzanthraceneAnimalsCarcinomaCell Line, TumorDisease SusceptibilityDown-RegulationFemaleImmunologic SurveillanceKiller Cells, NaturalLigandsMaleMembrane ProteinsMiceMice, Inbred C57BLMice, KnockoutMice, TransgenicNK Cell Lectin-Like Receptor Subfamily KPapillomaReceptors, ImmunologicReceptors, Natural Killer CellSkin NeoplasmsTetradecanoylphorbol AcetateT-LymphocytesTumor BurdenConceptsNKG2D downregulationNK cell-mediated cytotoxicityNatural killer cellsCell-mediated cytotoxicityInnate immune activationT cell defectsNKG2D engagementNatural cytotoxicityKiller cellsImmune activationReceptor NKG2DTumor immunosurveillanceCutaneous carcinogenesisTumor surveillanceT cellsReversible defectsRAE-1Normal epitheliumLigand expressionTumor resistanceCell defectsSustained expressionNKG2DImmunosurveillanceDownregulationThe Integration of Conventional and Unconventional T Cells that Characterizes Cell‐Mediated Responses
Pennington D, Vermijlen D, Wise E, Clarke S, Tigelaar R, Hayday A. The Integration of Conventional and Unconventional T Cells that Characterizes Cell‐Mediated Responses. Advances In Immunology 2005, 87: 27-59. PMID: 16102571, DOI: 10.1016/s0065-2776(05)87002-6.Peer-Reviewed Original ResearchCitationsMeSH Keywords and ConceptsConceptsUnconventional T cellsGene expression analysisConventional T cellsExtensive gene expression analysisT cellsExpression analysisRegulatory functionsCell-mediated immune responsesCell-mediated responsesT cell activityAntigen-specific responsesCellsInflammatory diseasesImmune responseImmunopathology
2003
Subset-specific, uniform activation among Vγ6/Vδ1+ γδ T cells elicited by inflammation
Roark C, Aydintug M, Lewis J, Yin X, Lahn M, Hahn Y, Born W, Tigelaar R, O’Brien R. Subset-specific, uniform activation among Vγ6/Vδ1+ γδ T cells elicited by inflammation. Journal Of Leukocyte Biology 2003, 75: 68-75. PMID: 14525969, DOI: 10.1189/jlb.0703326.Peer-Reviewed Original ResearchCitationsMeSH Keywords and ConceptsConceptsGamma delta T cell subsetT cell subsetsT cell receptorCell subsetsDelta antibodyActivation/memory phenotypeInvariant T cell receptorΓδ T cellsMemory phenotypeInflammatory responseT cellsFlow cytometryCell receptorInflammationMonoclonal antibodiesAntibodiesSelect tissuesCellsTissueSubsetVδ1ThymusThe inter-relatedness and interdependence of mouse T cell receptor γδ+ and αβ+ cells
Pennington D, Silva-Santos B, Shires J, Theodoridis E, Pollitt C, Wise E, Tigelaar R, Owen M, Hayday A. The inter-relatedness and interdependence of mouse T cell receptor γδ+ and αβ+ cells. Nature Immunology 2003, 4: 991-998. PMID: 14502287, DOI: 10.1038/ni979.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsMeSH KeywordsAnimalsCell DifferentiationCyclic AMP Response Element ModulatorDNA-Binding ProteinsFlow CytometryGene Expression ProfilingGenes, T-Cell ReceptorH-Y AntigenMaleMiceMice, Inbred C57BLMice, KnockoutMice, TransgenicReceptors, Antigen, T-Cell, alpha-betaReceptors, Antigen, T-Cell, gamma-deltaRepressor ProteinsReverse Transcriptase Polymerase Chain ReactionRNA, MessengerT-LymphocytesConceptsΑβ T cellsConventional αβ T cellsCell developmentFunctional potentialGene profilesT cell receptorT cellsMouse T-cell receptorΓδ T cell developmentT cell developmentT cell progenitorsCell receptorGene expressionCell progenitorsCell populationsImmune responseTCR specificityCellsReceptorsPotential interdependenceProgenitorsExpression
2001
Regulation of Cutaneous Malignancy by γδ T Cells
Girardi M, Oppenheim D, Steele C, Lewis J, Glusac E, Filler R, Hobby P, Sutton B, Tigelaar R, Hayday A. Regulation of Cutaneous Malignancy by γδ T Cells. Science 2001, 294: 605-609. PMID: 11567106, DOI: 10.1126/science.1063916.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsMeSH KeywordsAmino Acid SequenceAnimalsCarcinogensCell LineCytotoxicity, ImmunologicDimerizationEpidermisEpithelial CellsHistocompatibility Antigens Class IHumansImmunologic SurveillanceLigandsMembrane ProteinsMiceMice, Inbred C57BLMinor Histocompatibility AntigensMolecular Sequence DataNK Cell Lectin-Like Receptor Subfamily KProtein ConformationProtein FoldingReceptors, Antigen, T-Cell, alpha-betaReceptors, Antigen, T-Cell, gamma-deltaReceptors, ImmunologicReceptors, Natural Killer CellRecombinant Fusion ProteinsReverse Transcriptase Polymerase Chain ReactionSkin NeoplasmsT-Lymphocyte SubsetsConceptsT cellsGammadelta cellsLocal T cellsNatural killer cellsΓδ T cellsGammadelta T cellsCytolytic T cellsSkin carcinoma cellsNKG2D engagementMultiple regimensKiller cellsCutaneous malignanciesCutaneous carcinogenesisEpithelial malignanciesRAE-1Human MICAMalignancyCarcinoma cellsSkin cellsCellsNKG2DRegimensMiceEpitheliumCarcinogenesis
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Dermatology
PO Box 208059, 333 Cedar Street
New Haven, CT 06520-8059
United States