Abstract
Original language | English |
---|---|
Journal | Front. Immunol. |
Volume | 10 |
DOIs | |
Publication status | Published - 2019 |
Keywords
- inflammation
- inflammatory bowel disease
- Tbet
- Th1-like Tregs
- Treg cells
- CD45RB antigen
- gamma interferon
- interleukin 10
- interleukin 12p35
- interleukin 17
- interleukin 22
- interleukin 23p19
- interleukin 6
- transcription factor FOXP3
- transcription factor T bet
- tumor necrosis factor
- animal cell
- animal experiment
- animal model
- animal tissue
- Article
- CD3+ T lymphocyte
- CD4+ T lymphocyte
- cell proliferation
- cell proliferation assay
- cell subpopulation
- clinical article
- controlled study
- cytokine release
- disease course
- disease severity
- experimental colitis
- flow cytometry
- gene expression
- gene knockout
- histopathology
- human
- immune response
- male
- mouse
- nonhuman
- protein expression
- real time polymerase chain reaction
- regulatory T lymphocyte
- T lymphocyte activation
- Th1 cell
- ulcerative colitis
- upregulation
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Tbet Expression in Regulatory T Cells Is Required to Initiate Th1-Mediated Colitis : Frontiers in Immunology. / Di Giovangiulio, M.; Rizzo, A.; Franzè, E.; Caprioli, F.; Facciotti, F.; Onali, S.; Favale, A.; Stolfi, C.; Fehling, H.-J.; Monteleone, G.; Fantini, M.C.
In: Front. Immunol., Vol. 10, 2019.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Tbet Expression in Regulatory T Cells Is Required to Initiate Th1-Mediated Colitis
T2 - Frontiers in Immunology
AU - Di Giovangiulio, M.
AU - Rizzo, A.
AU - Franzè, E.
AU - Caprioli, F.
AU - Facciotti, F.
AU - Onali, S.
AU - Favale, A.
AU - Stolfi, C.
AU - Fehling, H.-J.
AU - Monteleone, G.
AU - Fantini, M.C.
N1 - Export Date: 26 February 2020 Correspondence Address: Fantini, M.C.; Department of Systems Medicine, University of Rome “Tor Vergata”Italy; email: m.fantini@med.uniroma2.it Chemicals/CAS: gamma interferon, 82115-62-6; interleukin 22, 457106-70-6, 478219-35-1, 554460-75-2 Tradenames: FACSVerse, Becton Dickinson Biosciences, United States Manufacturers: Becton Dickinson Biosciences, United States Funding details: Ministero dell’Istruzione, dell’Università e della Ricerca, MIUR, RBFR12VP3Q Funding details: Howard Hughes Medical Institute, HHMI Funding details: Ministero della Salute, GR-2011-02348069 Funding text 1: We acknowledge Prof. Alexander Rudensky, (HHMI, MD, USA) for kindly providing the FoxP3-eGFP-Cre knock-in mice. We also acknowledge Colantoni A and Ortenzi A (Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy, for technical assistance in the H&E staining of colonic sections). Funding. This work was supported by Futuro in ricerca, MIUR, RBFR12VP3Q and Giovani ricercatori, Ministero della Salute GR-2011-02348069. 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PY - 2019
Y1 - 2019
N2 - In normal conditions gut homeostasis is maintained by the suppressive activity of regulatory T cells (Tregs), characterized by the expression of the transcription factor FoxP3. In human inflammatory bowel disease, which is believed to be the consequence of the loss of tolerance toward antigens normally contained in the gut lumen, Tregs have been found to be increased and functionally active, thus pointing against their possible role in the pathogenesis of this immune-mediated disease. Though, in inflammatory conditions, Tregs have been shown to upregulate the T helper (Th) type 1-related transcription factor Tbet and to express the pro-inflammatory cytokine IFNγ, thus suggesting that at a certain point of the inflammatory process, Tregs might contribute to inflammation rather than suppress it. Starting from the observation that Tregs isolated from the lamina propria of active but not inactive IBD patients or uninflamed controls express Tbet and IFNγ, we investigated the functional role of Th1-like Tregs in the dextran sulfate model of colitis. As observed in human IBD, Th1-like Tregs were upregulated in the inflamed lamina propria of treated mice and the expression of Tbet and IFNγ in Tregs preceded the accumulation of conventional Th1 cells. By using a Treg-specific Tbet conditional knockout, we demonstrated that Tbet expression in Tregs is required for the development of colitis. Indeed, Tbet knockout mice developed milder colitis and showed an impaired Th1 immune response. In these mice not only the Tbet deficient Tregs but also the Tbet proficient conventional T cells showed reduced IFNγ expression. However, Tbet deficiency did not affect the Tregs suppressive capacity in vitro and in vivo in the adoptive transfer model of colitis. In conclusion here we show that Tbet expression by Tregs sustains the early phase of the Th1-mediated inflammatory response in the gut. © Copyright © 2019 Di Giovangiulio, Rizzo, Franzè, Caprioli, Facciotti, Onali, Favale, Stolfi, Fehling, Monteleone and Fantini.
AB - In normal conditions gut homeostasis is maintained by the suppressive activity of regulatory T cells (Tregs), characterized by the expression of the transcription factor FoxP3. In human inflammatory bowel disease, which is believed to be the consequence of the loss of tolerance toward antigens normally contained in the gut lumen, Tregs have been found to be increased and functionally active, thus pointing against their possible role in the pathogenesis of this immune-mediated disease. Though, in inflammatory conditions, Tregs have been shown to upregulate the T helper (Th) type 1-related transcription factor Tbet and to express the pro-inflammatory cytokine IFNγ, thus suggesting that at a certain point of the inflammatory process, Tregs might contribute to inflammation rather than suppress it. Starting from the observation that Tregs isolated from the lamina propria of active but not inactive IBD patients or uninflamed controls express Tbet and IFNγ, we investigated the functional role of Th1-like Tregs in the dextran sulfate model of colitis. As observed in human IBD, Th1-like Tregs were upregulated in the inflamed lamina propria of treated mice and the expression of Tbet and IFNγ in Tregs preceded the accumulation of conventional Th1 cells. By using a Treg-specific Tbet conditional knockout, we demonstrated that Tbet expression in Tregs is required for the development of colitis. Indeed, Tbet knockout mice developed milder colitis and showed an impaired Th1 immune response. In these mice not only the Tbet deficient Tregs but also the Tbet proficient conventional T cells showed reduced IFNγ expression. However, Tbet deficiency did not affect the Tregs suppressive capacity in vitro and in vivo in the adoptive transfer model of colitis. In conclusion here we show that Tbet expression by Tregs sustains the early phase of the Th1-mediated inflammatory response in the gut. © Copyright © 2019 Di Giovangiulio, Rizzo, Franzè, Caprioli, Facciotti, Onali, Favale, Stolfi, Fehling, Monteleone and Fantini.
KW - inflammation
KW - inflammatory bowel disease
KW - Tbet
KW - Th1-like Tregs
KW - Treg cells
KW - CD45RB antigen
KW - gamma interferon
KW - interleukin 10
KW - interleukin 12p35
KW - interleukin 17
KW - interleukin 22
KW - interleukin 23p19
KW - interleukin 6
KW - transcription factor FOXP3
KW - transcription factor T bet
KW - tumor necrosis factor
KW - animal cell
KW - animal experiment
KW - animal model
KW - animal tissue
KW - Article
KW - CD3+ T lymphocyte
KW - CD4+ T lymphocyte
KW - cell proliferation
KW - cell proliferation assay
KW - cell subpopulation
KW - clinical article
KW - controlled study
KW - cytokine release
KW - disease course
KW - disease severity
KW - experimental colitis
KW - flow cytometry
KW - gene expression
KW - gene knockout
KW - histopathology
KW - human
KW - immune response
KW - male
KW - mouse
KW - nonhuman
KW - protein expression
KW - real time polymerase chain reaction
KW - regulatory T lymphocyte
KW - T lymphocyte activation
KW - Th1 cell
KW - ulcerative colitis
KW - upregulation
U2 - 10.3389/fimmu.2019.02158
DO - 10.3389/fimmu.2019.02158
M3 - Article
VL - 10
JO - Front. Immunol.
JF - Front. Immunol.
SN - 1664-3224
ER -