Treg-mediated immunosuppression involves activation of the Notch-HES1 axis by membrane-bound TGF-beta.
Studies in humans and mice show an important role for Tregs in the control of immunological disorders. The mechanisms underlying the immunosuppressive functions of Tregs are not well understood. Here, we show that CD4+ T cells expressing Foxp3 and membrane-bound TGF-beta (TGF-beta(m+)Foxp3+), previously shown to be immunosuppressive in both allergic and autoimmune diseases, activate the Notch1-hairy and enhancer of split 1 (Notch1-HES1) axis in target cells. Soluble TGF-beta and cells secreting similar levels of soluble TGF-beta were unable to trigger Notch1 activation. Inhibition of Notch1 activation in vivo reversed the immunosuppressive functions of TGF-beta(m+)Foxp3+ cells, resulting in severe allergic airway inflammation. Integration of the TGF-beta and Notch1 pathways may be an important mechanism for the maintenance of immune homeostasis in the periphery.
Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
Marina
M
Ostroukhova
Zengbiao
Z
Qi
Timothy B
TB
Oriss
Barbara
B
Dixon-McCarthy
Prabir
P
Ray
Anuradha
A
Ray
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000276:immunology / Q000378:metabolism*; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D004789:Enzyme Activation; D051858:Forkhead Transcription Factors / Q000378:metabolism; D018398:Homeodomain Proteins / Q000276:immunology / Q000378:metabolism*; D007108:Immune Tolerance / Q000235:genetics*; D007249:Inflammation / Q000378:metabolism; D008024:Ligands; D008168:Lung / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051900:Smad3 Protein / Q000378:metabolism; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D000072056:Transcription Factor HES-1; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology*
D051792:Basic Helix-Loop-Helix Proteins; D051858:Forkhead Transcription Factors; D018398:Homeodomain Proteins; D008024:Ligands; D051881:Receptor, Notch1; D051900:Smad3 Protein; D000072056:Transcription Factor HES-1; D016212:Transforming Growth Factor beta; C498833:Foxp3 protein, mouse; C489734:Hes1 protein, mouse; C497791:Smad3 protein, mouse