Abstract
Effector T cell differentiation requires the simultaneous integration of multiple, and sometimes opposing, cytokine signals. We demonstrated mTOR's role in dictating the outcome of T cell fate. mTOR-deficient T cells displayed normal activation and IL-2 production upon initial stimulation. However, such cells failed to differentiate into T helper 1 (Th1), Th2, or Th17 effector cells. The inability to differentiate was associated with decreased STAT transcription factor activation and failure to upregulate lineage-specific transcription factors. Under normally activating conditions, T cells lacking mTOR differentiated into Foxp3(+) regulatory T cells. This was associated with hyperactive Smad3 activation in the absence of exogenous TGF-beta. Surprisingly, T cells selectively deficient in TORC1 do not divert to a regulatory T cell pathway, implicating both TORC1 and TORC2 in preventing the generation of regulatory T cells. Overall, our studies suggest that mTOR kinase signaling regulates decisions between effector and regulatory T cell lineage commitment.
Publication types
-
Research Support, N.I.H., Extramural
MeSH terms
-
Animals
-
Carrier Proteins / genetics
-
Carrier Proteins / immunology
-
Carrier Proteins / metabolism*
-
Cell Differentiation / immunology*
-
Interleukin-2 / biosynthesis
-
Interleukin-2 / immunology
-
Mice
-
Mice, Knockout
-
Phosphotransferases (Alcohol Group Acceptor) / genetics
-
Phosphotransferases (Alcohol Group Acceptor) / immunology
-
Phosphotransferases (Alcohol Group Acceptor) / metabolism*
-
Receptors, Antigen, T-Cell / immunology
-
Receptors, Antigen, T-Cell / metabolism
-
STAT Transcription Factors / immunology
-
STAT Transcription Factors / metabolism
-
Signal Transduction / immunology
-
T-Lymphocytes, Helper-Inducer / enzymology
-
T-Lymphocytes, Helper-Inducer / immunology*
-
T-Lymphocytes, Regulatory / enzymology
-
T-Lymphocytes, Regulatory / immunology*
-
TOR Serine-Threonine Kinases
-
Trans-Activators / immunology*
-
Trans-Activators / metabolism
-
Transcription Factors / genetics
-
Transcription Factors / immunology*
-
Transcription Factors / metabolism
-
Transforming Growth Factor beta / immunology
-
Transforming Growth Factor beta / metabolism
Substances
-
Carrier Proteins
-
Crtc1 protein, mouse
-
Crtc2 protein, mouse
-
Interleukin-2
-
Receptors, Antigen, T-Cell
-
STAT Transcription Factors
-
Trans-Activators
-
Transcription Factors
-
Transforming Growth Factor beta
-
Phosphotransferases (Alcohol Group Acceptor)
-
mTOR protein, mouse
-
TOR Serine-Threonine Kinases