Attenuation of canonical NF‐κB signaling maintains function and stability of human Treg. (28th May 2020)

• Record Type: Journal Article
• Authors: Ziegler, Liesa S.; Gerner, Marlene C.; Schmidt, Ralf L. J.; Trapin, Doris; Steinberger, Peter; Pickl, Winfried F.; Sillaber, Christian; Egger, Gerda; Schwarzinger, Ilse; Schmetterer, Klaus G.
• Is Part Of: FEBS journal. Volume 288:Number 2(2021)
• Page Start: 640
• Page End: 662
• Publication Date: 2020-05-28
• Subjects: immune tolerance -- NF‐κB signaling -- regulatory T cells -- TSDR; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pathology, Molecular -- Periodicals; 572
• DOI: 10.1111/febs.15361
• Languages: English
• ISSNs: 1742-464X

Abstract

Abstract : Nuclear factor 'κ‐light‐chain‐enhancer' of activated B cells (NF‐κB) signaling is a signaling pathway used by most immune cells to promote immunostimulatory functions. Recent studies have indicated that regulatory T cells (Treg) differentially integrate TCR‐derived signals, thereby maintaining their suppressive features. However, the role of NF‐κB signaling in the activation of human peripheral blood (PB) Treg has not been fully elucidated so far. We show that the activity of the master transcription factor forkhead box protein 3 (FOXP3) attenuates p65 phosphorylation and nuclear translocation of the NF‐κB proteins p50, p65, and c‐Rel following activation in human Treg. Using pharmacological and genetic inhibition of canonical NF‐κB signaling in FOXP3‐transgenic T cells and PB Treg from healthy donors as well as Treg from a patient with a primary NFKB1 haploinsufficiency, we validate that Treg activation and suppressive capacity is independent of NF‐κB signaling. Additionally, repression of residual NF‐κB signaling in Treg further enhances interleukin‐10 (IL‐10) production. Blockade of NF‐κB signaling can be exploited for the generation of in vitro induced Treg (iTreg) with enhanced suppressive capacity and functional stability. In this respect, dual blockade of mammalian target of rapamycin (mTOR) and NF‐κB signaling was accompanied by enhanced expression of the transcription factors FOXP1 and FOXP3 and demethylation of the Treg‐specific demethylated region compared to iTreg generated under mTOR blockade alone. Thus, we provide first insights into the role of NF‐κB signaling in human Treg. These findings could lead to strategies for the selective manipulation of Treg and the generation of improved iTreg for cellular therapy. Abstract : Human regulatory T cells (Treg) differentially integrate extracellular signals (e.g., mTOR, MAP‐kinase, and JAK/STAT signaling) compared to effector T cells. In this work, Ziegler et al . for the first time show that Treg also attenuate TCR‐triggered canonical NF‐κB signaling. This unique feature can also be exploited for the generation of inducible Treg. Combination of mTOR and NF‐κB blockade leads to the induction of Treg with increased suppressive capacity and improved functional stability.