1. Human resting CD4+ T cells are constitutively inhibited by TGF beta under steady-state conditions.
- Author
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Classen S, Zander T, Eggle D, Chemnitz JM, Brors B, Büchmann I, Popov A, Beyer M, Eils R, Debey S, and Schultze JL
- Subjects
- CD4-Positive T-Lymphocytes metabolism, Cell Differentiation genetics, Cell Differentiation immunology, Cells, Cultured, Culture Media, Serum-Free, Down-Regulation genetics, Down-Regulation immunology, Gene Targeting, Growth Inhibitors genetics, Humans, Immunophenotyping, Phosphorylation, Resting Phase, Cell Cycle genetics, Signal Transduction genetics, Signal Transduction immunology, Smad Proteins antagonists & inhibitors, Smad Proteins genetics, Smad Proteins metabolism, T-Lymphocyte Subsets metabolism, Transcription, Genetic, Transforming Growth Factor beta genetics, CD4-Positive T-Lymphocytes cytology, CD4-Positive T-Lymphocytes immunology, Growth Inhibitors physiology, Resting Phase, Cell Cycle immunology, T-Lymphocyte Subsets cytology, T-Lymphocyte Subsets immunology, Transforming Growth Factor beta physiology
- 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.
- Published
- 2007
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