6533b823fe1ef96bd127e0b0
RESEARCH PRODUCT
Repression of Cyclic Adenosine Monophosphate Upregulation Disarms and Expands Human Regulatory T Cells
Ria BaumgrassStephan GrabbeChristian BeckerTobias ScheelMartin VaethEdgar SchmittTobias BoppMatthias KleinFriederike Berberich-siebeltsubject
medicine.medical_specialtyRegulatory T cellImmunologychemical and pharmacologic phenomenaBiologyT-Lymphocytes RegulatoryMicechemistry.chemical_compoundInternal medicineCyclic AMPmedicineAnimalsHumansImmunology and AllergyCyclic adenosine monophosphatePsychological repressionCell ProliferationClonal AnergyNFATC Transcription FactorsClonal anergyPhosphodiesterasehemic and immune systemsUp-RegulationCell biologyEndocrinologymedicine.anatomical_structurechemistryHumanized mousecAMP-dependent pathwayCyclase activitydescription
Abstract The main molecular mechanism of human regulatory T cell (Treg)-mediated suppression has not been elucidated. We show in this study that cAMP represents a key regulator of human Treg function. Repression of cAMP production by inhibition of adenylate cyclase activity or augmentation of cAMP degradation through ectopic expression of a cAMP-degrading phosphodiesterase greatly reduces the suppressive activity of human Treg in vitro and in a humanized mouse model in vivo. Notably, cAMP repression additionally abrogates the anergic state of human Treg, accompanied by nuclear translocation of NFATc1 and induction of its short isoform NFATc1/αA. Treg expanded under cAMP repression, however, do not convert into effector T cells and regain their anergic state and suppressive activity upon proliferation. Together, these findings reveal the cAMP pathway as an attractive target for clinical intervention with Treg function.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2011-12-23 | The Journal of Immunology |