title: Developmental Progression and Interrelationship of Central and Effector Regulatory T Cell Subsets.
abstract: Resting central Tregs (cTregs) and activated effector Tregs (eTregs) are required for self-tolerance, but the heterogeneity and relationships within and between phenotypically distinct subsets of cTregs and eTregs are poorly understood. By extensive immune profiling and deep sequencing of TCR-β V regions, two subsets of cTregs, based on expression of Ly-6C, and three subsets of eTregs, based on distinctive expression of CD62L, CD69, and CD103, were identified. Ly-6C(+) cTregs exhibited lower basal activation, expressed on average lower affinity TCRs, and less efficiently developed into eTregs when compared with Ly-6C(-) cTregs. The dominant TCR Vβs of Ly-6C(+) cTregs were shared by eTregs at a low frequency. A single TCR clonotype was also identified that was largely restricted to Ly-6C(+) cTregs, even under conditions that promoted the development of eTregs. Collectively, these findings indicate that some Ly-6C(+) cTregs may persist as a lymphoid-specific subset, with minimal potential to develop into highly activated eTregs, whereas other cTregs readily develop into eTregs. In contrast, subsets of CD62L(lo) eTregs showed higher clonal expansion and were more highly interrelated than cTreg subsets based on their TCR-β repertoires, but exhibited varied immune profiles. The CD62L(lo) CD69(-) CD103(-) eTreg subset displayed properties of a transitional intermediate between cTregs and more activated eTreg subsets. Thus, eTreg subsets appear to exhibit substantial flexibility, most likely in response to environmental cues, to adopt defined immune profiles that are expected to optimize suppression of autoreactive T cells.
authors.affiliation: Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL 33136; and.
authors.forename: Kevin H
authors.initials: KH
authors.lastname: Toomer
authors.affiliation: Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL 33136; and.
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Yuan
authors.affiliation: Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL 33136; and.
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL 33136; and.
authors.forename: Michael J
authors.identifier: 0000-0002-3673-5370
authors.initials: MJ
authors.lastname: Dee
authors.affiliation: Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL 33136; and.
authors.forename: Aixin
authors.identifier: 0000-0002-0557-8077
authors.initials: A
authors.lastname: Yu
authors.affiliation: Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL 33136; and Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL 33136 tmalek@med.miami.edu.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Malek
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics; D000950:Antigens, Ly / Q000235:genetics; D019674:Genes, T-Cell Receptor beta; D059014:High-Throughput Nucleotide Sequencing; D039001:Integrin alpha Chains / Q000172:deficiency / Q000235:genetics; D019041:L-Selectin / Q000235:genetics; D037181:Lectins, C-Type / Q000172:deficiency / Q000235:genetics; D051379:Mice; D017634:Self Tolerance; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000502:physiology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D000950:Antigens, Ly; D039001:Integrin alpha Chains; D019041:L-Selectin; D037181:Lectins, C-Type; D000099192:CD69 Antigens; C494192:Ly-6C antigen, mouse; C091367:alpha E integrins