Helios Enhances Treg Cell Function in Cooperation With FoxP3.
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.


CONCLUSIONS
Our findings indicate that Helios enhances induced Treg cell function in cooperation with FoxP3.
Chiba University Graduate School of Medicine, Chiba, Japan.
Hiroaki
H
Takatori
Chiba University Graduate School of Medicine, Chiba, Japan.
Hirotoshi
H
Kawashima
Chiba University Graduate School of Medicine, Chiba, Japan.
Ayako
A
Matsuki
Chiba University Graduate School of Medicine, Chiba, Japan.
Kazuyuki
K
Meguro
Chiba University Graduate School of Medicine, Chiba, Japan.
Shigeru
S
Tanaka
Chiba University Graduate School of Medicine, Chiba, Japan.
Taro
T
Iwamoto
Chiba University Graduate School of Medicine, Chiba, Japan.
Yoshie
Y
Sanayama
Chiba University Graduate School of Medicine, Chiba, Japan.
Natsuko
N
Nishikawa
Chiba University Graduate School of Medicine, Chiba, Japan.
Tomohiro
T
Tamachi
Chiba University Graduate School of Medicine, Chiba, Japan.
Kei
K
Ikeda
Chiba University Graduate School of Medicine, Chiba, Japan.
Akira
A
Suto
Chiba University Graduate School of Medicine, Chiba, Japan.
Kotaro
K
Suzuki
Chiba University Graduate School of Medicine, Chiba, Japan.
Shin-ichiro
S
Kagami
Chiba University Graduate School of Medicine, Chiba, Japan.
Koichi
K
Hirose
Tokyo University of Science, Noda Campus, Chiba, Japan.
Masato
M
Kubo
RIKEN Yokohama Institute, Kanagawa, Japan.
Shohei
S
Hori
Chiba University Graduate School of Medicine, Chiba, Japan.
Hiroshi
H
Nakajima
D000069594:Abatacept; D000328:Adult; D000368:Aged; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D018501:Antirheumatic Agents / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D016022:Case-Control Studies; D004268:DNA-Binding Proteins / Q000276:immunology; D005260:Female; D051858:Forkhead Transcription Factors / Q000276:immunology*; D006801:Humans; D051740:Ikaros Transcription Factor / Q000276:immunology*; D018796:Immunoconjugates / Q000627:therapeutic use; D015850:Interleukin-6 / Q000276:immunology / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*; D014157:Transcription Factors / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000494:pharmacology; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D004268:DNA-Binding Proteins; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C111431:IKZF2 protein, human; D018796:Immunoconjugates; D015850:Interleukin-6; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; C491746:Zfpn1a2 protein, mouse; D051740:Ikaros Transcription Factor; D000069594:Abatacept; C502936:tocilizumab