title: Divergent Phenotypes of Human Regulatory T Cells Expressing the Receptors TIGIT and CD226.
abstract: Regulatory T cells (Tregs) play a central role in counteracting inflammation and autoimmunity. A more complete understanding of cellular heterogeneity and the potential for lineage plasticity in human Treg subsets may identify markers of disease pathogenesis and facilitate the development of optimized cellular therapeutics. To better elucidate human Treg subsets, we conducted direct transcriptional profiling of CD4(+)FOXP3(+)Helios(+) thymic-derived Tregs and CD4(+)FOXP3(+)Helios(-) T cells, followed by comparison with CD4(+)FOXP3(-)Helios(-) T conventional cells. These analyses revealed that the coinhibitory receptor T cell Ig and ITIM domain (TIGIT) was highly expressed on thymic-derived Tregs. TIGIT and the costimulatory factor CD226 bind the common ligand CD155. Thus, we analyzed the cellular distribution and suppressive activity of isolated subsets of CD4(+)CD25(+)CD127(lo/-) T cells expressing CD226 and/or TIGIT. We observed TIGIT is highly expressed and upregulated on Tregs after activation and in vitro expansion, and is associated with lineage stability and suppressive capacity. Conversely, the CD226(+)TIGIT(-) population was associated with reduced Treg purity and suppressive capacity after expansion, along with a marked increase in IL-10 and effector cytokine production. These studies provide additional markers to delineate functionally distinct Treg subsets that may help direct cellular therapies and provide important phenotypic markers for assessing the role of Tregs in health and disease.
authors.affiliation: Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610;
authors.forename: Christopher A
authors.identifier: http://orcid.org/0000-0002-5364-6935
authors.initials: CA
authors.lastname: Fuhrman
authors.affiliation: Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610;
authors.forename: Wen-I
authors.initials: WI
authors.lastname: Yeh
authors.affiliation: Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610;
authors.forename: Howard R
authors.initials: HR
authors.lastname: Seay
authors.affiliation: Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610;
authors.forename: Priya
authors.initials: P
authors.lastname: Saikumar Lakshmi
authors.affiliation: Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Gainesville, FL 32603;
authors.forename: Gaurav
authors.initials: G
authors.lastname: Chopra
authors.affiliation: Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610;
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610;
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Perry
authors.affiliation: Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Gainesville, FL 32603;
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: McClymont
authors.affiliation: Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Gainesville, FL 32603;
authors.forename: Mahesh
authors.initials: M
authors.lastname: Yadav
authors.affiliation: Diabetes Center and Department of Medicine, University of California, San Francisco, San Francisco CA 94143;
authors.forename: Maria-Cecilia
authors.initials: MC
authors.lastname: Lopez
authors.affiliation: Diabetes Center and Department of Medicine, University of California, San Francisco, San Francisco CA 94143;
authors.forename: Henry V
authors.initials: HV
authors.lastname: Baker
authors.affiliation: Precision Medicine-Bioanalytical, Pfizer, Cambridge, MA 02139; and.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Pfizer Research and Development Business Technologies, Cambridge, MA 02139.
authors.forename: Yizheng
authors.initials: Y
authors.lastname: Li
authors.affiliation: Pfizer Research and Development Business Technologies, Cambridge, MA 02139.
authors.forename: Maryann
authors.initials: M
authors.lastname: Whitley
authors.affiliation: Precision Medicine-Bioanalytical, Pfizer, Cambridge, MA 02139; and.
authors.forename: David
authors.initials: D
authors.lastname: von Schack
authors.affiliation: Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610;
authors.forename: Mark A
authors.initials: MA
authors.lastname: Atkinson
authors.affiliation: Diabetes Center and Department of Medicine, University of California, San Francisco, San Francisco CA 94143;
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Bluestone
authors.affiliation: Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610; tbrusko@ufl.edu.
authors.forename: Todd M
authors.identifier: http://orcid.org/0000-0003-2878-9296
authors.initials: TM
authors.lastname: Brusko
mesh_terms: D000328:Adult; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D015704:CD4 Antigens / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation; D019070:Cell Lineage / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology; D020869:Gene Expression Profiling; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics / Q000276:immunology; D016130:Immunophenotyping; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D008024:Ligands; D008213:Lymphocyte Activation; D008875:Middle Aged; D010641:Phenotype; D061251:Primary Cell Culture; D011485:Protein Binding; D011971:Receptors, Immunologic / Q000235:genetics / Q000276:immunology*; D011991:Receptors, Virus / Q000235:genetics / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*; D059467:Transcriptome / Q000276:immunology*; D000098862:T Lineage-Specific Activation Antigen 1
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; D000098862:T Lineage-Specific Activation Antigen 1; D015704:CD4 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C111431:IKZF2 protein, human; C508609:IL10 protein, human; D008024:Ligands; D011971:Receptors, Immunologic; D011991:Receptors, Virus; C534712:TIGIT protein, human; C066100:poliovirus receptor; D016753:Interleukin-10; D051740:Ikaros Transcription Factor