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In Vitro Differentiation of Human CD4+FOXP3+ Induced Regulatory T Cells (iTregs) from Naïve CD4+ T Cells Using a TGF-β-containing Protocol
Published on: December 30, 2016
HTLV-1 bZIP factor induces inflammation through labile Foxp3 expression.
Nanae Yamamoto-Taguchi1, Yorifumi Satou, Paola Miyazato
1Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Kyoto, Japan.
Plos Pathogens
|September 27, 2013
Summary
The Human T-cell leukemia virus type 1 (HTLV-1) HBZ gene promotes inflammation by enhancing induced regulatory T (iTreg) cells. These cells lose Foxp3 expression and produce inflammatory cytokines, contributing to HTLV-1-associated diseases.
Area of Science:
- Immunology
- Virology
- Molecular Biology
Background:
- Human T-cell leukemia virus type 1 (HTLV-1) causes inflammatory diseases like HAM/TSP.
- The HTLV-1 basic leucine zipper factor (HBZ) gene is expressed in infected cells and promotes regulatory T (Treg) cell expansion.
- Treg cell plasticity allows conversion to inflammatory phenotypes, producing cytokines like IFN-γ.
Purpose of the Study:
- To investigate the role of HBZ in HTLV-1-associated chronic inflammation.
- To analyze the mechanisms by which HBZ influences Treg cell function and plasticity.
- To understand the contribution of HBZ-mediated T-cell responses to HTLV-1 pathogenesis.
Main Methods:
- Analysis of lymphocyte infiltration in HBZ-transgenic (HBZ-Tg) mice.
- Assessment of CD4+ T cell adhesion and migration.
- Measurement of IFN-γ production in Foxp3-expressing and non-expressing T cells.
- Evaluation of Helios expression in Treg cells from HBZ-Tg mice and HAM/TSP patients.
- Analysis of Foxp3 gene methylation in Treg cells.
Main Results:
- HBZ-Tg mice exhibited lymphocyte infiltration in skin, lung, and intestine.
- HBZ-expressing CD4+ T cells showed enhanced adhesion and migration.
- Foxp3-negative CD4+ T cells produced significantly more IFN-γ in HBZ-Tg mice.
- Reduced Helios expression indicated predominant induced Treg (iTreg) cells in HBZ-Tg mice and HAM/TSP patients.
- Hypermethylation of the Foxp3 gene's CNS2 region in HBZ-Tg mice confirmed iTreg cell characteristics.
- Treg cells in HBZ-Tg mice lost Foxp3 expression and produced excess IFN-γ, unlike stable natural Treg cells in the thymus.
Conclusions:
- HBZ promotes the generation of iTreg cells that can convert to inflammatory Foxp3-negative T cells producing IFN-γ.
- HBZ-induced pro-inflammatory CD4+ T cell phenotype is implicated in HTLV-1-associated inflammation.
- Understanding HBZ's role in Treg plasticity is crucial for developing therapeutic strategies against HTLV-1-driven inflammatory diseases.
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