학술논문
The [S1P.sub.1]-mTOR axis directs the reciprocal differentiation of [T.sub.H]1 and [T.sub.reg] cells
Document Type
Report
Source
Nature Immunology. November 1, 2010, Vol. 11 Issue 11, p1047, 11 p.
Subject
Language
English
ISSN
1529-2908
Abstract
[CD4.sup.+] helper T cells are central regulators of adaptive immune responses. In response to antigen stimulation, naive [CD4.sup.+] T cells proliferate and differentiate into T helper type 1 ([T.sub.H]1) cells, [...]
Naive [CD4.sup.+] T cells differentiate into diverse effector and regulatory lineages to orchestrate immunity and tolerance. Here we found that the differentiation of proinflammatory T helper type 1 ([T.sub.H]1) cells and anti-inflammatory Foxp[3.sup.+] regulatory T cells ([T.sub.reg] cells) was reciprocally regulated by [S1P.sub.1], a receptor for the bioactive lipid sphingosine 1- phosphate (S1P). [S1P.sub.1] inhibited the generation of extrathymic and natural [T.sub.reg] cells while driving [T.sub.H]1 development in a reciprocal manner and disrupted immune homeostasis. [S1P.sub.1] signaled through the kinase mTOR and antagonized the function of transforming growth factor- β mainly by attenuating sustained activity of the signal transducer Smad3. [S1P.sub.1] function was dependent on endogenous sphingosine kinase activity. Notably, two seemingly unrelated immunosuppressants, FTY720 and rapamycin, targeted the same [S1P.sub.1] and mTOR pathway to regulate the dichotomy between [T.sub.H]1 cells and [T.sub.reg] cells. Our studies establish an [S1P.sub.1]- mTOR axis that controls T cell lineage specification.
Naive [CD4.sup.+] T cells differentiate into diverse effector and regulatory lineages to orchestrate immunity and tolerance. Here we found that the differentiation of proinflammatory T helper type 1 ([T.sub.H]1) cells and anti-inflammatory Foxp[3.sup.+] regulatory T cells ([T.sub.reg] cells) was reciprocally regulated by [S1P.sub.1], a receptor for the bioactive lipid sphingosine 1- phosphate (S1P). [S1P.sub.1] inhibited the generation of extrathymic and natural [T.sub.reg] cells while driving [T.sub.H]1 development in a reciprocal manner and disrupted immune homeostasis. [S1P.sub.1] signaled through the kinase mTOR and antagonized the function of transforming growth factor- β mainly by attenuating sustained activity of the signal transducer Smad3. [S1P.sub.1] function was dependent on endogenous sphingosine kinase activity. Notably, two seemingly unrelated immunosuppressants, FTY720 and rapamycin, targeted the same [S1P.sub.1] and mTOR pathway to regulate the dichotomy between [T.sub.H]1 cells and [T.sub.reg] cells. Our studies establish an [S1P.sub.1]- mTOR axis that controls T cell lineage specification.