Foxp3(+) T cells expressing RORγt represent a stable regulatory T-cell effector lineage with enhanced suppressive capacity during intestinal inflammation
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Foxp3(+) T cells expressing RORγt represent a stable regulatory T-cell effector lineage with enhanced suppressive capacity during intestinal inflammation. / Yang, B-H; Hagemann, S; Mamareli, P; Lauer, U; Hoffmann, U; Beckstette, M; Föhse, L; Prinz, I; Pezoldt, J; Suerbaum, S; Sparwasser, T; Hamann, A; Floess, S; Huehn, J; Lochner, M.
in: MUCOSAL IMMUNOL, Jahrgang 9, Nr. 2, 03.2016, S. 444-57.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Foxp3(+) T cells expressing RORγt represent a stable regulatory T-cell effector lineage with enhanced suppressive capacity during intestinal inflammation
AU - Yang, B-H
AU - Hagemann, S
AU - Mamareli, P
AU - Lauer, U
AU - Hoffmann, U
AU - Beckstette, M
AU - Föhse, L
AU - Prinz, I
AU - Pezoldt, J
AU - Suerbaum, S
AU - Sparwasser, T
AU - Hamann, A
AU - Floess, S
AU - Huehn, J
AU - Lochner, M
PY - 2016/3
Y1 - 2016/3
N2 - 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.
AB - 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.
KW - Adoptive Transfer
KW - Animals
KW - CTLA-4 Antigen/genetics
KW - Carrier Proteins/genetics
KW - Cell Lineage
KW - Colitis/genetics
KW - Colon/immunology
KW - DNA-Binding Proteins/genetics
KW - Epigenesis, Genetic/immunology
KW - Female
KW - Forkhead Transcription Factors/genetics
KW - Glucocorticoid-Induced TNFR-Related Protein/genetics
KW - Immunity, Mucosal/drug effects
KW - Inflammation
KW - Lymphocyte Activation
KW - Mice
KW - Mice, Inbred C57BL
KW - Mice, Knockout
KW - Nerve Tissue Proteins/genetics
KW - Nuclear Receptor Subfamily 1, Group F, Member 3/genetics
KW - Signal Transduction
KW - T-Lymphocytes, Regulatory/immunology
KW - Transcription Factors/genetics
U2 - 10.1038/mi.2015.74
DO - 10.1038/mi.2015.74
M3 - SCORING: Journal article
C2 - 26307665
VL - 9
SP - 444
EP - 457
JO - MUCOSAL IMMUNOL
JF - MUCOSAL IMMUNOL
SN - 1933-0219
IS - 2
ER -