Antigen-specific transforming growth factor β-induced treg cells, but not natural treg cells, ameliorate autoimmune arthritis in mice by shifting the Th17/treg cell balance from Th17 predominance to treg cell predominance

Ning Kong, Qin Lan, Maogen Chen, Julie Wang, Wei Shi, David A. Horwitz, Valerie Quesniaux, Bernhard Ryffel, Zhongmin Liu, David Brand, Hejian Zou, Song Guo Zheng

Research output: Contribution to journalArticle

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Abstract

Objective Transferred CD4+CD25+FoxP3+ Treg cells can prevent autoimmune disease, but generally fail to ameliorate established disease. This study was undertaken to compare the effects of antigen-specific Treg cells induced with interleukin-2 (IL-2) and transforming growth factor β (TGFβ) ex vivo (induced Treg [iTreg] cells) to the effects of equivalent expanded thymus-derived natural Treg (nTreg) cells on established collagen-induced arthritis (CIA). Methods CIA was induced in DBA/1 mice by immunization with type II collagen (CII), and before or shortly after immunization, mice were treated with iTreg or nTreg cells that were generated or expanded in vitro. Clinical scores were determined. Inflammatory responses were determined by measuring the levels of anti-CII antibody in the serum and examining the histologic features of the mouse joints. The Th1/Th17-mediated autoreactive response was evaluated by determining the cytokine profile of the draining lymph node (LN) cells of the mice by flow cytometry. Results Following transfer, nTreg cells exhibited decreased FoxP3 and Bcl-2 expression and decreased suppressive activity, and many converted to Th17 cells. In contrast, transferred iTreg cells were more numerous, retained FoxP3 expression and their suppressive activity in the presence of IL-6, and were resistant to Th17 conversion. Notably, 10 days after the transfer of donor iTreg cells, predominance was shifted from Th17 cells to Treg cells in the draining LNs of recipient mice. Conclusion These findings provide evidence that transferred TGFβ-induced iTreg cells are more stable and functional than nTreg cells in mice with established autoimmunity. Moreover, iTreg cells can have tolerogenic effects even in the presence of ongoing inflammation. The therapeutic potential of human iTreg cells in subjects with chronic, immune-mediated inflammatory diseases should be investigated.

Original languageEnglish (US)
Pages (from-to)2548-2558
Number of pages11
JournalArthritis and rheumatism
Volume64
Issue number8
DOIs
StatePublished - Aug 1 2012

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Th17 Cells
Transforming Growth Factors
Regulatory T-Lymphocytes
Arthritis
Antigens
Experimental Arthritis
Immunization
Inbred DBA Mouse
Collagen Type II
Autoimmunity
Thymus Gland
Autoimmune Diseases
Interleukin-2
Anti-Idiotypic Antibodies

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Rheumatology
  • Immunology
  • Pharmacology (medical)

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Antigen-specific transforming growth factor β-induced treg cells, but not natural treg cells, ameliorate autoimmune arthritis in mice by shifting the Th17/treg cell balance from Th17 predominance to treg cell predominance. / Kong, Ning; Lan, Qin; Chen, Maogen; Wang, Julie; Shi, Wei; Horwitz, David A.; Quesniaux, Valerie; Ryffel, Bernhard; Liu, Zhongmin; Brand, David; Zou, Hejian; Zheng, Song Guo.

In: Arthritis and rheumatism, Vol. 64, No. 8, 01.08.2012, p. 2548-2558.

Research output: Contribution to journalArticle

Kong, Ning ; Lan, Qin ; Chen, Maogen ; Wang, Julie ; Shi, Wei ; Horwitz, David A. ; Quesniaux, Valerie ; Ryffel, Bernhard ; Liu, Zhongmin ; Brand, David ; Zou, Hejian ; Zheng, Song Guo. / Antigen-specific transforming growth factor β-induced treg cells, but not natural treg cells, ameliorate autoimmune arthritis in mice by shifting the Th17/treg cell balance from Th17 predominance to treg cell predominance. In: Arthritis and rheumatism. 2012 ; Vol. 64, No. 8. pp. 2548-2558.
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abstract = "Objective Transferred CD4+CD25+FoxP3+ Treg cells can prevent autoimmune disease, but generally fail to ameliorate established disease. This study was undertaken to compare the effects of antigen-specific Treg cells induced with interleukin-2 (IL-2) and transforming growth factor β (TGFβ) ex vivo (induced Treg [iTreg] cells) to the effects of equivalent expanded thymus-derived natural Treg (nTreg) cells on established collagen-induced arthritis (CIA). Methods CIA was induced in DBA/1 mice by immunization with type II collagen (CII), and before or shortly after immunization, mice were treated with iTreg or nTreg cells that were generated or expanded in vitro. Clinical scores were determined. Inflammatory responses were determined by measuring the levels of anti-CII antibody in the serum and examining the histologic features of the mouse joints. The Th1/Th17-mediated autoreactive response was evaluated by determining the cytokine profile of the draining lymph node (LN) cells of the mice by flow cytometry. Results Following transfer, nTreg cells exhibited decreased FoxP3 and Bcl-2 expression and decreased suppressive activity, and many converted to Th17 cells. In contrast, transferred iTreg cells were more numerous, retained FoxP3 expression and their suppressive activity in the presence of IL-6, and were resistant to Th17 conversion. Notably, 10 days after the transfer of donor iTreg cells, predominance was shifted from Th17 cells to Treg cells in the draining LNs of recipient mice. Conclusion These findings provide evidence that transferred TGFβ-induced iTreg cells are more stable and functional than nTreg cells in mice with established autoimmunity. Moreover, iTreg cells can have tolerogenic effects even in the presence of ongoing inflammation. The therapeutic potential of human iTreg cells in subjects with chronic, immune-mediated inflammatory diseases should be investigated.",
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T1 - Antigen-specific transforming growth factor β-induced treg cells, but not natural treg cells, ameliorate autoimmune arthritis in mice by shifting the Th17/treg cell balance from Th17 predominance to treg cell predominance

AU - Kong, Ning

AU - Lan, Qin

AU - Chen, Maogen

AU - Wang, Julie

AU - Shi, Wei

AU - Horwitz, David A.

AU - Quesniaux, Valerie

AU - Ryffel, Bernhard

AU - Liu, Zhongmin

AU - Brand, David

AU - Zou, Hejian

AU - Zheng, Song Guo

PY - 2012/8/1

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N2 - Objective Transferred CD4+CD25+FoxP3+ Treg cells can prevent autoimmune disease, but generally fail to ameliorate established disease. This study was undertaken to compare the effects of antigen-specific Treg cells induced with interleukin-2 (IL-2) and transforming growth factor β (TGFβ) ex vivo (induced Treg [iTreg] cells) to the effects of equivalent expanded thymus-derived natural Treg (nTreg) cells on established collagen-induced arthritis (CIA). Methods CIA was induced in DBA/1 mice by immunization with type II collagen (CII), and before or shortly after immunization, mice were treated with iTreg or nTreg cells that were generated or expanded in vitro. Clinical scores were determined. Inflammatory responses were determined by measuring the levels of anti-CII antibody in the serum and examining the histologic features of the mouse joints. The Th1/Th17-mediated autoreactive response was evaluated by determining the cytokine profile of the draining lymph node (LN) cells of the mice by flow cytometry. Results Following transfer, nTreg cells exhibited decreased FoxP3 and Bcl-2 expression and decreased suppressive activity, and many converted to Th17 cells. In contrast, transferred iTreg cells were more numerous, retained FoxP3 expression and their suppressive activity in the presence of IL-6, and were resistant to Th17 conversion. Notably, 10 days after the transfer of donor iTreg cells, predominance was shifted from Th17 cells to Treg cells in the draining LNs of recipient mice. Conclusion These findings provide evidence that transferred TGFβ-induced iTreg cells are more stable and functional than nTreg cells in mice with established autoimmunity. Moreover, iTreg cells can have tolerogenic effects even in the presence of ongoing inflammation. The therapeutic potential of human iTreg cells in subjects with chronic, immune-mediated inflammatory diseases should be investigated.

AB - Objective Transferred CD4+CD25+FoxP3+ Treg cells can prevent autoimmune disease, but generally fail to ameliorate established disease. This study was undertaken to compare the effects of antigen-specific Treg cells induced with interleukin-2 (IL-2) and transforming growth factor β (TGFβ) ex vivo (induced Treg [iTreg] cells) to the effects of equivalent expanded thymus-derived natural Treg (nTreg) cells on established collagen-induced arthritis (CIA). Methods CIA was induced in DBA/1 mice by immunization with type II collagen (CII), and before or shortly after immunization, mice were treated with iTreg or nTreg cells that were generated or expanded in vitro. Clinical scores were determined. Inflammatory responses were determined by measuring the levels of anti-CII antibody in the serum and examining the histologic features of the mouse joints. The Th1/Th17-mediated autoreactive response was evaluated by determining the cytokine profile of the draining lymph node (LN) cells of the mice by flow cytometry. Results Following transfer, nTreg cells exhibited decreased FoxP3 and Bcl-2 expression and decreased suppressive activity, and many converted to Th17 cells. In contrast, transferred iTreg cells were more numerous, retained FoxP3 expression and their suppressive activity in the presence of IL-6, and were resistant to Th17 conversion. Notably, 10 days after the transfer of donor iTreg cells, predominance was shifted from Th17 cells to Treg cells in the draining LNs of recipient mice. Conclusion These findings provide evidence that transferred TGFβ-induced iTreg cells are more stable and functional than nTreg cells in mice with established autoimmunity. Moreover, iTreg cells can have tolerogenic effects even in the presence of ongoing inflammation. The therapeutic potential of human iTreg cells in subjects with chronic, immune-mediated inflammatory diseases should be investigated.

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