Based on studies in knockout mice, several inhibitory factors such as TGFbeta, IL-10, or CTLA-4 have been implicated as gate keepers of adaptive immune responses. Lack of these inhibitory molecules leads to massive inflammatory responses mainly mediated by activated T cells. In humans, the integration of these inhibitory signals for keeping T cells at a resting state is less well understood. To elucidate this regulatory network, we assessed early genome-wide transcriptional changes during serum deprivation in human mature CD4(+) T cells. The most striking observation was a "TGFbeta loss signature" defined by down-regulation of many known TGFbeta target genes. Moreover, numerous novel TGFbeta target genes were identified that are under the suppressive control of TGFbeta. Expression of these genes was up-regulated once TGFbeta signaling was lost during serum deprivation and again suppressed upon TGFbeta reconstitution. Constitutive TGFbeta signaling was corroborated by demonstrating phosphorylated SMAD2/3 in resting human CD4(+) T cells in situ, which were dephosphorylated during serum deprivation and rephosphorylated by minute amounts of TGFbeta. Loss of TGFbeta signaling was particularly important for T cell proliferation induced by low-level TCR and costimulatory signals. We suggest TGFbeta to be the most prominent factor actively keeping human CD4(+) T cells at a resting state.
%0 Journal Article
%1 Classen2007
%A Classen, Sabine
%A Zander, Thomas
%A Eggle, Daniela
%A Chemnitz, Jens M.
%A Brors, Benedikt
%A Büchmann, Ingrid
%A Popov, Alexey
%A Beyer, Marc
%A Eils, Roland
%A Debey, Svenja
%A Schultze, Joachim L.
%D 2007
%J J Immunol
%K /&/ CD4-Positive Cell Cells, Culture Cultured; Differentiation, Down-Regulation, Factor G0 Gene Genetic; Growth Humans; Immunophenotyping; Inhibitors, Media, Phase, Phosphorylation; Proteins, Serum-Free; Signal Smad Subsets, T-Lymphocyte T-Lymphocytes, Targeting; Transcription, Transduction, Transforming antagonists beta, cytology/immunology/metabolism; genetics/immunology; genetics/physiology genetics/physiology; inhibitors/genetics/metabolism;
%N 11
%P 6931--6940
%T Human resting CD4+ T cells are constitutively inhibited by TGF beta under steady-state conditions.
%V 178
%X Based on studies in knockout mice, several inhibitory factors such as TGFbeta, IL-10, or CTLA-4 have been implicated as gate keepers of adaptive immune responses. Lack of these inhibitory molecules leads to massive inflammatory responses mainly mediated by activated T cells. In humans, the integration of these inhibitory signals for keeping T cells at a resting state is less well understood. To elucidate this regulatory network, we assessed early genome-wide transcriptional changes during serum deprivation in human mature CD4(+) T cells. The most striking observation was a "TGFbeta loss signature" defined by down-regulation of many known TGFbeta target genes. Moreover, numerous novel TGFbeta target genes were identified that are under the suppressive control of TGFbeta. Expression of these genes was up-regulated once TGFbeta signaling was lost during serum deprivation and again suppressed upon TGFbeta reconstitution. Constitutive TGFbeta signaling was corroborated by demonstrating phosphorylated SMAD2/3 in resting human CD4(+) T cells in situ, which were dephosphorylated during serum deprivation and rephosphorylated by minute amounts of TGFbeta. Loss of TGFbeta signaling was particularly important for T cell proliferation induced by low-level TCR and costimulatory signals. We suggest TGFbeta to be the most prominent factor actively keeping human CD4(+) T cells at a resting state.
@article{Classen2007,
__markedentry = {[bbrors:6]},
abstract = {Based on studies in knockout mice, several inhibitory factors such as TGFbeta, IL-10, or CTLA-4 have been implicated as gate keepers of adaptive immune responses. Lack of these inhibitory molecules leads to massive inflammatory responses mainly mediated by activated T cells. In humans, the integration of these inhibitory signals for keeping T cells at a resting state is less well understood. To elucidate this regulatory network, we assessed early genome-wide transcriptional changes during serum deprivation in human mature CD4(+) T cells. The most striking observation was a "TGFbeta loss signature" defined by down-regulation of many known TGFbeta target genes. Moreover, numerous novel TGFbeta target genes were identified that are under the suppressive control of TGFbeta. Expression of these genes was up-regulated once TGFbeta signaling was lost during serum deprivation and again suppressed upon TGFbeta reconstitution. Constitutive TGFbeta signaling was corroborated by demonstrating phosphorylated SMAD2/3 in resting human CD4(+) T cells in situ, which were dephosphorylated during serum deprivation and rephosphorylated by minute amounts of TGFbeta. Loss of TGFbeta signaling was particularly important for T cell proliferation induced by low-level TCR and costimulatory signals. We suggest TGFbeta to be the most prominent factor actively keeping human CD4(+) T cells at a resting state.},
added-at = {2015-04-09T12:36:21.000+0200},
author = {Classen, Sabine and Zander, Thomas and Eggle, Daniela and Chemnitz, Jens M. and Brors, Benedikt and B{\"{u}}chmann, Ingrid and Popov, Alexey and Beyer, Marc and Eils, Roland and Debey, Svenja and Schultze, Joachim L.},
biburl = {https://www.bibsonomy.org/bibtex/282a3e93cb0e7db8909fbfe258b59682c/bbrors},
institution = {Department of Internal Medicine I, Molecular Tumor Biology and Tumor Immunology, University of Cologne, Cologne, Germany.},
interhash = {902a832c02c7b3ea4bcc9f315b80deb0},
intrahash = {82a3e93cb0e7db8909fbfe258b59682c},
journal = {J Immunol},
keywords = {/&/ CD4-Positive Cell Cells, Culture Cultured; Differentiation, Down-Regulation, Factor G0 Gene Genetic; Growth Humans; Immunophenotyping; Inhibitors, Media, Phase, Phosphorylation; Proteins, Serum-Free; Signal Smad Subsets, T-Lymphocyte T-Lymphocytes, Targeting; Transcription, Transduction, Transforming antagonists beta, cytology/immunology/metabolism; genetics/immunology; genetics/physiology genetics/physiology; inhibitors/genetics/metabolism;},
language = {eng},
medline-pst = {ppublish},
month = Jun,
number = 11,
owner = {bbrors},
pages = {6931--6940},
pii = {178/11/6931},
pmid = {17513742},
timestamp = {2015-04-09T12:36:21.000+0200},
title = {Human resting CD4+ T cells are constitutively inhibited by TGF beta under steady-state conditions.},
volume = 178,
year = 2007
}