A critical function for TGF-β signaling in the development of natural CD4+CD25+Foxp3+ regulatory T cells

Abstract

The molecular mechanisms directing the development of 'natural' CD4+CD25+Foxp3+ regulatory T cells (T(reg) cells) in the thymus are not thoroughly understood. We show here that conditional deletion of transforming growth factor-beta receptor I (TbetaRI) in T cells blocked the appearance of CD4+CD25+Foxp3+ thymocytes at postnatal days 3-5. Paradoxically, however, beginning 1 week after birth, the same TbetaRI-mutant mice showed accelerated expansion of thymic CD4+CD25+Foxp3+ populations. This rapid recovery of Foxp3+ thymocytes was attributable mainly to overproduction of and heightened responsiveness to interleukin 2, as genetic ablation of interleukin 2 in TbetaRI-mutant mice resulted in a complete absence of CD4+CD25+Foxp3+ cells from the thymus and periphery. Thus, transforming growth factor-beta signaling is critical to the thymic development of natural CD4+CD25+Foxp3+ T(reg) cells.

MicroRNAs targeting TGFβ signalling underlie the regulatory T cell defect in multiple sclerosis

“…Interestingly, similar observations of reduced Treg function and TCR diversity has been reported in mice deficient in TGFb signalling (Gorelik and Flavell, 2000;Marie et al, 2005Marie et al, , 2006Liu et al, 2008;Ouyang et al, 2010). Currently, it is unclear whether the observed defect is a result of disrupted Treg machinery or a lack of Treg clonal diversity.…”

“…The mechanisms for Treg defects in patients with multiple sclerosis are unknown. Interestingly, adult mice deficient in TGFb signalling exhibit a Treg phenotype with normal numbers, decreased suppressive function, and an incomplete TCR repertoire (Gorelik and Flavell, 2000;Marie et al, 2005Marie et al, , 2006Liu et al, 2008;Ouyang et al, 2010), mirroring the observations seen in patients with multiple sclerosis. We hypothesized that dysregulated miRNAs in the naïve CD4 T cells of patients with multiple sclerosis modulate the TGFb-signalling pathway, resulting in defective Tregs and enhanced susceptibility to developing multiple sclerosis.…”

“…Although there has been some controversy as to whether patients with multiple sclerosis have a reduced number of Tregs, the majority of studies suggest that the defect is not in number but in function (Viglietta et al, 2004;Haas et al, 2005Haas et al, , 2007Huan et al, 2005;Kumar et al, 2006;Venken et al, 2008). In mice with deficiencies in TGFb signalling, the number of Tregs in adult mice is normal; however, the number of Tregs postnatally is significantly reduced (Marie et al, 2005;Liu et al, 2008;Ouyang et al, 2010). This limited pool of Tregs, which are CD25 + , proliferate in response to IL-2 resulting in normal numbers of Tregs.…”

“…This limited pool of Tregs, which are CD25 + , proliferate in response to IL-2 resulting in normal numbers of Tregs. This expanded pool of Tregs has a diminished capacity to suppress effector T cells as evidenced by the uncontrolled autoimmunity observed in mice with deficiencies in TGFb signalling (Gorelik and Flavell, 2000;Marie et al, 2006;Liu et al, 2008). The inability of Tregs from TGFb signalling-impaired mice to suppress autoimmunity has been attributed to decreased FOXP3 expression and a decreased repertoire of Tregs.…”

“…The differentially expressed miRNAs negatively regulated the TGFb pathway, resulting in a reduced capacity of naïve CD4 T cells to differentiate into Tregs, yet the function of the limited repertoire of Tregs appeared normal. The observation that Treg numbers appear normal in patients with multiple sclerosis in most studies is probably due to the fact that high expression of CD25 allows the Tregs that do develop to proliferate and appear normal in number, as observed in mice with defected TGFb signalling (Liu et al, 2008). As compromising the TGFb signalling pathway reduces the Treg repertoire, which results in an inability to control autoimmunity and patients with multiple sclerosis have a reduced Treg repertoire, these TGFbtargeting miRNAs impair TGFb signalling, dampen Treg development, enhancing susceptibility to developing multiple sclerosis.…”