Helios Enhances Treg Cell Function in Cooperation With FoxP3.

Abstract

OBJECTIVE:

Helios+FoxP3+CD4+ (Helios+) Treg cells are believed to be involved in the regulation of various autoimmune diseases; however, the regulatory mechanisms underlying the development of Helios+ Treg cells remain uncertain. This study was undertaken to elucidate the regulatory mechanisms of Helios expression in CD4+ T cells and its roles in transforming growth factor β (TGFβ)-induced Treg cell function.

METHODS:

We examined the expression of Helios in CD4+ T cells in patients with rheumatoid arthritis by DNA microarray analysis before and after treatment with biologic agents. We also examined the effect of interleukin-6 (IL-6) and TGFβ on Helios expression in CD4+ T cells in humans and mice. The effect of forced expression of Helios on murine induced Treg cell function was also examined. The role of FoxP3 in the induction and function of Helios was assessed by using CD4+ T cells from FoxP3-deficient scurfy mice.

RESULTS:

Tocilizumab, but not tumor necrosis factor (TNF) inhibitors or abatacept, increased Helios expression in CD4+ T cells in patients with a good response. IL-6 inhibited the TGFβ-induced development of Helios+ induced Treg cells in both humans and mice. Both cell-intrinsic FoxP3 expression and TGFβ signaling were required for Helios induction in murine induced Treg cells. The forced expression of Helios enhanced the expression of various Treg cell-related molecules and the suppressive function in murine induced Treg cells. Helios-mediated enhancement of the suppressive function of induced Treg cells was obvious in FoxP3-sufficient CD4+ T cells but not in FoxP3-deficient CD4+ T cells.

CONCLUSION:

Our findings indicate that Helios enhances induced Treg cell function in cooperation with FoxP3.

• Authors: Hiroaki Takatori, Hirotoshi Kawashima, Ayako Matsuki, Kazuyuki Meguro, Shigeru Tanaka, Taro Iwamoto, Yoshie Sanayama, Natsuko Nishikawa, Tomohiro Tamachi, Kei Ikeda, Akira Suto, Kotaro Suzuki, Shin-ichiro Kagami, Koichi Hirose, Masato Kubo, Shohei Hori, Hiroshi Nakajima
• Journal: Arthritis & rheumatology (Hoboken, N.J.) (Arthritis Rheumatol) Vol. 67 Issue 6 Pg. 1491-502 (Jun 2015) ISSN: 2326-5205 [Electronic] United States
• PMID: 25733061 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015, American College of Rheumatology.

Chemical References

• Antibodies, Monoclonal, Humanized
• Antirheumatic Agents
• DNA-Binding Proteins
• FOXP3 protein, human
• Forkhead Transcription Factors
• Foxp3 protein, mouse
• IKZF2 protein, human
• Immunoconjugates
• Interleukin-6
• Transcription Factors
• Transforming Growth Factor beta
• Tumor Necrosis Factor-alpha
• Zfpn1a2 protein, mouse
• Ikaros Transcription Factor
• Abatacept
• tocilizumab

Topics

• Abatacept
• Adult
• Aged
• Animals
• Antibodies, Monoclonal, Humanized (therapeutic use)
• Antirheumatic Agents (therapeutic use)
• Arthritis, Rheumatoid (drug therapy, immunology)
• CD4-Positive T-Lymphocytes (drug effects, immunology)
• Case-Control Studies
• DNA-Binding Proteins (immunology)
• Female
• Forkhead Transcription Factors (immunology)
• Humans
• Ikaros Transcription Factor (immunology)
• Immunoconjugates (therapeutic use)
• Interleukin-6 (immunology, pharmacology)
• Male
• Middle Aged
• Oligonucleotide Array Sequence Analysis
• T-Lymphocytes, Regulatory (drug effects, immunology)
• Transcription Factors (immunology)
• Transforming Growth Factor beta (immunology, pharmacology)
• Treatment Outcome
• Tumor Necrosis Factor-alpha (antagonists & inhibitors)