%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 }