IL-1R1 is expressed on both Helios(+) and Helios(-) FoxP3(+) CD4(+) T cells in the rheumatic joint.

Synovial fluid from rheumatic joints displays a well-documented enrichment of forkhead box protein 3 (FoxP3)(+) regulatory T cells (tissue Tregs ). However, we have previously demonstrated that the mere frequency of FoxP3 expressing cells cannot predict suppressive function. Instead, extrinsic factors and the functional heterogeneity of FoxP3(+) Tregs complicate the picture. Here, we investigated FoxP3(+) Tregs from blood and synovial fluid of patients with rheumatic disease in relation to Helios expression by assessing phenotypes, proliferative potential and cytokine production by flow cytometry. Our aim was to investigate the discriminatory potential of Helios when studying FoxP3(+) Tregs in an inflammatory setting. We demonstrate that the majority of the synovial FoxP3(+) CD4(+) T cells in patients with inflammatory arthritis expressed Helios. Helios(+) FoxP3(+) Tregs displayed a classical Treg phenotype with regard to CD25 and cytotoxic T lymphocyte-associated antigen (CTLA)-4 expression and a demethylated Treg -specific demethylated region (TSDR). Furthermore, Helios(+) FoxP3(+) T cells were poor producers of the effector cytokines interferon (IFN)-γ and tumour necrosis factor (TNF), as well as of the anti-inflammatory cytokine interleukin (IL)-10. The less abundant Helios(-) FoxP3(+) T cell subset was also enriched significantly in the joint, displayed a overlapping phenotype to the double-positive Treg cells with regard to CTLA-4 expression, but differed by their ability to secrete IL-10, IFN-γ and TNF upon T cell receptor (TCR) cross-linking. We also demonstrate a striking enrichment of IL-1R1 expression in synovial CD4(+) T cells that was restricted to the CD25-expressing FoxP3 population, but independent of Helios. IL-1R1 expression appears to define a tissue Treg cell phenotype together with the expression of CD25, glucocorticoid-induced TNF receptor family-related gene (GITR) and CTLA-4.

Müller M ，Herrath J ，Malmström V 《-》

Foxp3+ Helios+ regulatory T cells are expanded in active systemic lupus erythematosus.

Alexander T ，Sattler A ，Templin L ，Kohler S ，Groß C ，Meisel A ，Sawitzki B ，Burmester GR ，Arnold R ，Radbruch A ，Thiel A ，Hiepe F ... -  《-》

Helios Enhances Treg Cell Function in Cooperation With FoxP3.

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

Takatori H ，Kawashima H ，Matsuki A ，Meguro K ，Tanaka S ，Iwamoto T ，Sanayama Y ，Nishikawa N ，Tamachi T ，Ikeda K ，Suto A ，Suzuki K ，Kagami S ，Hirose K ，Kubo M ，Hori S ，Nakajima H ... -  《-》

FOXP3 expression in blood, synovial fluid and synovial tissue during inflammatory arthritis and intra-articular corticosteroid treatment.

Raghavan S ，Cao D ，Widhe M ，Roth K ，Herrath J ，Engström M ，Roncador G ，Banham AH ，Trollmo C ，Catrina AI ，Malmström V ... -  《-》

FOXP3+Helios+ Regulatory T Cells, Immune Activation, and Advancing Disease in HIV-Infected Children.

Khaitan A ，Kravietz A ，Mwamzuka M ，Marshed F ，Ilmet T ，Said S ，Ahmed A ，Borkowsky W ，Unutmaz D ... -  《-》