#cparse("/super/config/super.config.vm") #cparse ("/includes/site.config.fhtml") #cparse("${directoryRoot}/config/2col.config.vm") ## siteSection - tab to highlight on top navigation #set ($siteSection = "lipidomics update") #set ($siteSubSection = "archives") ## Webtrends #set($WT_cg_n = "Lipidomics Update") #set($WT_cg_s = "Articles") #cparse("${superIncludes}/super.before-doctype.fhtml") #cparse("${directoryIncludes}/doctype.fhtml") #cparse("${superIncludes}/super.head-top.fhtml") Sphingosine 1-phosphate signaling: Treg or not Treg, that is the question : $siteName #set($metaDescription = "S1P1 activates the mTOR-Akt pathway to suppress Treg-cell differentiation and activity.") #cparse("${directoryIncludes}/metalink.fhtml") #cparse("${directoryIncludes}/style.fhtml") #cparse("${superIncludes}/super.head-bottom.fhtml") #cparse("${superIncludes}/super.body-top.fhtml") #cparse("${directoryIncludes}/header.fhtml") #cparse("${common}/includes/clearfloats.fhtml")

Sphingosine 1-phosphate signaling: Treg or not Treg, that is the question

Lipidomics Gateway (22 July 2009) [doi:10.1038/lipidmaps.2009.18]

S1P1 activates the mTOR-Akt pathway to suppress Treg-cell differentiation and activity.

Regulatory T (Treg) cells help maintain immunological tolerance by antagonizing conventional T (Tconv)-cell responses. Their suppressive effects must be halted to permit adaptive immune responses, but unrestrained Treg-cell activity can lead to impaired immunity. The mechanism that regulates Treg cells has remained largely uncharacterized. In Nature Immunology, Hongbo Chi and colleagues now report that sphingosine 1-phosphate receptor 1 (S1P1 ) signals through the mTORAkt pathway to repress Treg-cell differentiation and activity.

S1P1 was previously shown to regulate T-cell trafficking, but its importance in Treg cells had not been elucidated. Targeted deletion of S1P1 in T cells upregulated FoxP3 expression — a transcription factor involved in the differentiation of CD4+CD25+FoxP3- precursor cells into mature Treg cells — and increased the thymic Treg-cell population. Overexpression of S1P1 shrank the Treg-cell population and blocked precursor cells from differentiating into mature Treg cells, indicating that S1P1 antagonizes Treg-cell differentiation.

Moreover, S1P1 also impairs Treg-cell function. When S1P1-knockout or wild-type Treg cells were mixed with Tconv cells, the knockout cells were better able to suppress Tconv-cell proliferation and IL-2 secretion. Transgenic expression of S1P1 elicited the opposite effect. Indeed, as a result of the defective Treg-cell function, S1P1-transgenic mice developed autoimmune reactions in vivo that were associated with enhanced activation of Tconv cells.

Expression of IL-2 and activation of the T-cell antigen receptor (TCR) both modulate the differentiation and function of Treg cells by activating the Akt, Erk and STAT5 signaling pathways. Overexpression of S1P1 significantly upregulated the activity of Akt, but not Erk or STAT5. Intriguingly, blocking mTOR–Akt pathway signaling in cells overexpressing S1P1 restored their ability to suppress Tconv-cell proliferation. Furthermore, loss of S1P1 attenuated Akt activation in mature Treg cells following treatment with IL-2. Thus, S1P1-mediated activation of the mTOR–Akt pathway inhibits Treg-cell differentiation and activity.

S1P1–mTOR–Akt signaling in Treg cells mediates immune tolerance by antagonizing their differentiation and function. Remarkably, S1P1 mRNA levels declined rapidly in Tconv cells following TCR or IL-2 induction, and S1P1 was not required for cell proliferation or Akt activation in these cells. In contrast, the amount of S1P1 mRNA declined gradually in Treg cells. Expression of KLF2, a transcription factor essential for S1P1 expression in thymocytes, exhibited a similar expression pattern to that of S1P1. Thus, KLF2 may contribute to the differential regulation of S1P1 in Treg and Tconv cells. It will be important to determine the extent to which KLF2 is required for maintaining immunological tolerance and to elucidate the signals that modulate KLF2 expression.

Emily J. Chenette

- Copyright © 2009 Nature Publishing Group, a division of Macmillan Publishers Limited; used with permission

References:

Reference

  1. Liu, G. et al. The receptor S1P1 overrides regulatory T cell-mediated immune suppression through Akt-mTOR.

    Nature Immunology 10, 769-777 (2009). doi:10.1038/ni.1743

Further reading

  1. Ohkura, N. and Sakaguchi, S. A novel modifier of regulatory T cells.

    Nature Immunology 10, 685-686 (2009). doi:10.1038/ni0709-685

#cparse("${directoryIncludes}/search.fhtml") #cparse("${directoryIncludes}/links.fhtml") #cparse("${directoryIncludes}/resources.fhtml")
#cparse("${common}/includes/clearfloats.fhtml") #cparse("${directoryIncludes}/footer.fhtml") #cparse("${superIncludes}/super.body-bottom.fhtml")