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.
- /&/
- antagonists
- beta,
- cd4-positive
- cell
- cells,
- culture
- cultured;
- cytology/immunology/metabolism;
- differentiation,
- down-regulation,
- factor
- g0
- gene
- genetic;
- genetics/immunology;
- genetics/physiology
- genetics/physiology;
- growth
- humans;
- immunophenotyping;
- inhibitors,
- inhibitors/genetics/metabolism;
- media,
- phase,
- phosphorylation;
- proteins,
- serum-free;
- signal
- smad
- subsets,
- t-lymphocyte
- t-lymphocytes,
- targeting;
- transcription,
- transduction,
- transforming
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