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Peng, Y. et al. TGF- regulates in vivo expansion of Foxp3-expressing CD4+CD25+ regulatory T cells responsible for protection against diabetes. Proc. Natl. Acad. Sci. USA 101, 4572−4577

Section of Immunobiology and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 04/2004; 101(13):4572-7. DOI: 10.1073/pnas.0400810101
Source: PubMed

ABSTRACT

CD4+CD25+ regulatory T cells are essential in the protection from organ-specific autoimmune diseases. In the pancreas, they inhibit actions of autoreactive T cells and thereby prevent diabetes progression. The signals that control the generation, the maintenance, or the expansion of regulatory T cell pool in vivo remain poorly understood. Here we show that a transient pulse of transforming growth factor beta (TGF-beta) in the islets during the priming phase of diabetes is sufficient to inhibit disease onset by promoting the expansion of intraislet CD4+CD25+ T cell pool. Approximately 40-50% of intraislet CD4+ T cells expressed the CD25 marker and exhibited characteristics of regulatory T cells including small size, high level of intracellular CTLA-4, expression of Foxp3, and transfer of protection against diabetes. Results from in vivo incorporation of BrdUrd revealed that the generation of a high frequency of regulatory T cells in the islets is due to in situ expansion upon TGF-beta expression. Thus, these findings demonstrate a previously uncharacterized mechanism by which TGF-beta inhibits autoimmune diseases via regulation of the size of the CD4+CD25+ regulatory T cell pool in vivo.

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    • "The cytokine is instrumental in almost every compartment of the immune system [29], inducing for example B cell class switching to IgA [30] [31] and driving myeloid cells into a more tumor-promoting phenotype [32]. But its effects on T cells are perhaps the most prominent, in particular its ability to stimulate naïve CD4 + T cells to differentiate into Foxp3 + Treg that can suppress effector T cell activation and proliferation [33] [34], and prolong allograft survival upon adoptive transfer into recipient animals [35]. The level of Foxp3 expression by Treg correlates with functional suppressive capacity [36] and stability of Foxp3 expression is essential for maintenance of a regulatory phenotype [37]. "

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    • "The cytokine is instrumental in almost every compartment of the immune system [29], inducing for example B cell class switching to IgA [30] [31] and driving myeloid cells into a more tumor-promoting phenotype [32]. But its effects on T cells are perhaps the most prominent, in particular its ability to stimulate naïve CD4 + T cells to differentiate into Foxp3 + Treg that can suppress effector T cell activation and proliferation [33] [34], and prolong allograft survival upon adoptive transfer into recipient animals [35]. The level of Foxp3 expression by Treg correlates with functional suppressive capacity [36] and stability of Foxp3 expression is essential for maintenance of a regulatory phenotype [37]. "
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    • "In our previous study [29] and that performed by Akinci et al. [30] decreased TGFβ1 levels were found in Hashimoto's thyroiditis. On the other hand, over-expression of TGFβ1 in pancreatic islets expands the T reg population and protects non-obese diabetic mice against type I diabetes — another T cell-mediated disease [31]. The two polymorphisms at codon 10 and 25 are within the 29- amino acid signal sequence. "
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