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TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function
Liang Zhou1, Jared E Lopes, Mark M W Chong
1The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, New York 10016, USA.
Nature
|March 28, 2008
Summary
Transforming growth factor-beta (TGF-beta) concentration dictates T helper 17 (T(H)17) and regulatory T (T(reg)) cell differentiation. Low TGF-beta promotes T(H)17 cells, while high TGF-beta favors T(reg) cells by balancing RORgammat and Foxp3 transcription factors.
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- T helper 17 (T(H)17) cells and regulatory T (T(reg)) cells have opposing roles in immunity and inflammation.
- Both T(H)17 and T(reg) cell differentiation require transforming growth factor-beta (TGF-beta) but are regulated by distinct transcription factors, RORgammat and Foxp3, respectively.
- The precise mechanism by which TGF-beta orchestrates the differentiation of these opposing T cell subsets has remained unclear.
Purpose of the Study:
- To elucidate how transforming growth factor-beta (TGF-beta) concentration-dependently regulates the differentiation of T helper 17 (T(H)17) and regulatory T (T(reg)) cells.
- To investigate the interplay between RORgammat and Foxp3 transcription factors in T cell lineage commitment.
- To understand the role of cytokines like IL-6, IL-21, and IL-23 in modulating T cell differentiation.
Main Methods:
- In vitro differentiation of naive CD4+ T cells under varying TGF-beta concentrations.
- Analysis of transcription factor expression (RORgammat and Foxp3) and cytokine production (IL-17).
- Assessment of T cell populations in the small intestinal lamina propria of mice.
Main Results:
- TGF-beta regulates T(H)17 and T(reg) cell differentiation in a concentration-dependent manner.
- Low TGF-beta concentrations promote T(H)17 cell differentiation by upregulating IL-23 receptor (Il23r) expression, while high concentrations favor T(reg) cells.
- Foxp3 can inhibit RORgammat function, and this inhibition is relieved by cytokines IL-6, IL-21, and IL-23, promoting T(H)17 cell differentiation.
Conclusions:
- The differentiation fate of antigen-stimulated T cells into either T(H)17 or T(reg) cells is determined by the cytokine milieu and the resulting balance between RORgammat and Foxp3.
- TGF-beta concentration is a critical factor in directing T cell lineage commitment.
- This study provides a molecular mechanism for how opposing T cell populations are generated to maintain immune homeostasis.
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