Human resting CD4+ T cells are constitutively inhibited by TGF beta under steady-state conditions.
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.
Classen
Sabine
S
Department of Internal Medicine I, Molecular Tumor Biology and Tumor Immunology, University of Cologne, Cologne, Germany.
Zander
Thomas
T
Eggle
Daniela
D
Chemnitz
Jens M
JM
Brors
Benedikt
B
Büchmann
Ingrid
I
Popov
Alexey
A
Beyer
Marc
M
Eils
Roland
R
Debey
Svenja
S
Schultze
Joachim L
JL
D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D018390:Gene Targeting; D006131:Growth Inhibitors / Q000235:genetics / Q000502:physiology*; D006801:Humans; D016130:Immunophenotyping; D010766:Phosphorylation; D016192:Resting Phase, Cell Cycle / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D051785:Smad Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology*
D016895:Culture Media, Serum-Free; D006131:Growth Inhibitors; D051785:Smad Proteins; D016212:Transforming Growth Factor beta