title: Foxp3(+) T cells expressing RORγt represent a stable regulatory T-cell effector lineage with enhanced suppressive capacity during intestinal inflammation.
abstract: Foxp3 (forkhead box P3 transcription factor)-expressing regulatory T cells (Tregs) are essential for immunological tolerance, best illustrated by uncontrolled effector T-cell responses and autoimmunity upon loss of Foxp3 expression. Tregs can adopt specific effector phenotypes upon activation, reflecting the diversity of functional demands in the different tissues of the body. Here, we report that Foxp3(+)CD4(+) T cells coexpressing retinoic acid-related orphan receptor-γt (RORγt), the master transcription factor for T helper type 17 (Th17) cells, represent a stable effector Treg lineage. Transcriptomic and epigenetic profiling revealed that Foxp3(+)RORγt(+) T cells display signatures of both Tregs and Th17 cells, although the degree of similarity was higher to Foxp3(+)RORγt(-) Tregs than to Foxp3(-)RORγt(+) T cells. Importantly, Foxp3(+)RORγt(+) T cells were significantly demethylated at Treg-specific epigenetic signature genes such as Foxp3, Ctla-4, Gitr, Eos, and Helios, suggesting that these cells have a stable regulatory rather than inflammatory function. Indeed, adoptive transfer of Foxp3(+)RORγt(+) T cells in the T-cell transfer colitis model confirmed their Treg function and lineage stability in vivo, and revealed an enhanced suppressive capacity as compared with Foxp3(+)RORγt(-) Tregs. Thus, our data suggest that RORγt expression in Tregs contributes to an optimal suppressive capacity during gut-specific immune responses, rendering Foxp3(+)RORγt(+) T cells as an important effector Treg subset in the intestinal system.
authors: Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors: B-H
authors: BH
authors: Yang
authors: Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research; a joint venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany.
authors: S
authors: S
authors: Hagemann
authors: Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research; a joint venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany.
authors: P
authors: P
authors: Mamareli
authors: Deutsches Rheuma-Forschungszentrum and Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors: U
authors: U
authors: Lauer
authors: Deutsches Rheuma-Forschungszentrum and Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors: U
authors: U
authors: Hoffmann
authors: Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors: M
authors: M
authors: Beckstette
authors: Institute of Immunology, Hannover Medical School, Hannover, Germany.
authors: L
authors: L
authors: Föhse
authors: Institute of Immunology, Hannover Medical School, Hannover, Germany.
authors: I
authors: I
authors: Prinz
authors: Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors: J
authors: J
authors: Pezoldt
authors: Institute for Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany.
authors: S
authors: S
authors: Suerbaum
authors: Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research; a joint venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany.
authors: T
authors: T
authors: Sparwasser
authors: Deutsches Rheuma-Forschungszentrum and Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors: A
authors: A
authors: Hamann
authors: Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors: S
authors: S
authors: Floess
authors: Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors: J
authors: J
authors: Huehn
authors: Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research; a joint venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany.
authors: M
authors: M
authors: Lochner
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D060908:CTLA-4 Antigen / Q000235:genetics / Q000276:immunology; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology; D019070:Cell Lineage; D003092:Colitis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D003106:Colon / Q000276:immunology / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology; D044127:Epigenesis, Genetic / Q000276:immunology; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology*; D053450:Glucocorticoid-Induced TNFR-Related Protein / Q000235:genetics / Q000276:immunology; D018928:Immunity, Mucosal / Q000187:drug effects*; D007249:Inflammation; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000276:immunology; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology / Q000637:transplantation; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology
chemical_list: D060908:CTLA-4 Antigen; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053450:Glucocorticoid-Induced TNFR-Related Protein; D009419:Nerve Tissue Proteins; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C106544:Tnfrsf18 protein, mouse; D014157:Transcription Factors; C491746:Zfpn1a2 protein, mouse; C118760:Zfpn1a4 protein, mouse