Abstract
Foxp3 expressing regulatory T (Treg) cells, as the central negative regulator of adaptive immune system, are essential to suppress immune response and maintain immune homeostasis. However, the function of Treg cells is frequently compromised in autoimmunity and hyper-activated in infections and tumor microenvironments. Thus, manipulating Treg cells becomes a promising therapeutic strategy for treating various diseases. Here we reported that inhibition of Cdk8/Cdk19 activity by small molecule inhibitors CCT251921 or Senexin A greatly promoted the differentiation of Treg cells and the expression of Treg signature genes, such as Foxp3, CTLA4, PD-1, and GITR. Mechanistically, we found that the augmented Treg cell differentiation was due to sensitized TGF-β signaling by Cdk8/Cdk19 inhibition, which was associated with attenuation of IFN-γ-Stat1 signaling and enhancement of phosphorylated Smad2/3. Importantly, treatment with Cdk8/Cdk19 inhibitor CCT251921 significantly increased Treg population and ameliorated autoimmune symptoms in an experimental autoimmune encephalomyelitis (EAE) model. Taken together, our study reveals a novel role of Cdk8/Cdk19 in Treg cell differentiation and provides a potential target for Treg cell based therapeutics.
Highlights
Treg cells are the central negative regulator of adaptive immune system, which is essential for immune tolerance and immune homeostasis [1]
We found that CCT251921 treatment significantly increased Foxp3+ Treg cell population with a very low concentration of 10 nM and the beneficial effect saturated at 50 nM (Figures 1A,B)
To further confirm the promotion of Foxp3+ Treg cell differentiation is dependent on Cdk8/Cdk19 inhibition, another selective and structurally different Cdk8/Cdk19 inhibitor Senexin A [10] was used in the ex vivo T cell differentiation system
Summary
Treg cells are the central negative regulator of adaptive immune system, which is essential for immune tolerance and immune homeostasis [1]. The function of Treg cells is frequently compromised in autoimmunity and hyper-activated in tumor microenvironments. Targeting Treg cells becomes a promising therapeutic strategy to treat many diseases [2]. By upregulating Treg cell function, it can be used to treat autoimmunity such as multiple sclerosis, graft-vs.-host disease, systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA). Down-regulation of Treg cells can be applied to boost immune system to fight against infection and cancer. Understanding the molecular regulation of Treg differentiation will provide valuable targets for modulating Treg cell function
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