Treg-mediated immunosuppression involves activation of the Notch-HES1 axis by membrane-bound TGF-β
Marina Ostroukhova, Zengbiao Qi, Timothy B. Oriss, Barbara Dixon-McCarthy, rabir Ray,, Anuradha Ray
Marina Ostroukhova, Zengbiao Qi, Timothy B. Oriss, Barbara Dixon-McCarthy, rabir Ray,, Anuradha Ray
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Research Article Immunology

Treg-mediated immunosuppression involves activation of the Notch-HES1 axis by membrane-bound TGF-β

Abstract

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-β (TGF-βm+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-β and cells secreting similar levels of soluble TGF-β were unable to trigger Notch1 activation. Inhibition of Notch1 activation in vivo reversed the immunosuppressive functions of TGF-βm+Foxp3+ cells, resulting in severe allergic airway inflammation. Integration of the TGF-β and Notch1 pathways may be an important mechanism for the maintenance of immune homeostasis in the periphery.

Authors

Marina Ostroukhova, Zengbiao Qi, Timothy B. Oriss, Barbara Dixon-McCarthy, rabir Ray,, Anuradha Ray

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Figure 6

Membrane-bound TGF-β, but not soluble TGF-β, induces interaction between cleaved Notch1 and pSmad3.

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Membrane-bound TGF-β, but not soluble TGF-β, induces interaction between...
DO11.10 CD4+ T cells were cocultured with TGF-βm+ cells, TGF-βm– cells, naive CD4+ T cells, or soluble TGF-β (2 ng/ml) for 24 hours, and cell extracts were prepared. The extracts were subjected to immunoprecipitation using anti-pSmad3 or isotype control (with TGF-βm+ cells). The immunoprecipitates were analyzed by immunoblotting with antibody against cleaved Notch1, and the blot was stripped and reprobed with anti-pSmad3. While all lysates contained similar levels of Smad3, which is constitutively expressed in cells (data not shown), Smad3 was phosphorylated in the presence of TGF-βm+ cells, TGF-βm– cells, or soluble TGF-β, but not naive cells.